Archive for the ‘Cardiac Stem Cells’ Category

CAIRO 22 September 2019: Renowned Professor of Cardiothoracic surgery Magdi Yacoub said that the foundation stone of a heart center in Cairo will be laid soon. The center will provide cardiac care.

In an interview with Egypt Today, the Egyptian-British cardiothoracic surgeonsaid that an inauguration ceremony of the Cairo center will beheldin January 2020, and will beattended by a large number of parliamentarians, senior doctors and statesmen to support the center and urge Egyptians to donate.

The MagdiYacoub Global Heart Foundation launched a campaign in May to raise fund for the new center.

A set of remarkable scientists and public figures took part in the campaign such as Professor MagdyIshak, and Egyptian Ambassador to the United States Yasser Reda, among others.

The MagdiYacoub Global Heart Foundation supports Aswan heart centre in Upper Egypt and is raising funds for the future MagdiYacoubglobal heart centre in Cairo.

Besides providing urgently needed cardiac care, the centers impact the region and continent by advancing scientific understanding through research and building human health capacities with training programs.

The new center will cost an estimate of $150 million and will include 300 beds, hence expected to upgrade network care capacity from 33,000 to 140,000 outpatients and from 4,000 to 17,000 inpatients annually.

Moreover, the training capacity will grow from 550 to over 2300, dramatically increasing the sectors workforce.

Yacoub was among the first three surgeons to perform an open heart surgery in Nigeria in 1974. In 1986, he was part of the team that developed the techniques of the heart-lung transplantation at the National Heart and Lung Institute.

He also led a British research team at Harefield hospital in 2007, aiming to grow a part of the human heart using stem cells. These efforts were all exerted in order to overcome the shortage of heart transplant donations.

Read the rest here:
Cairo heart center to be inaugurated January: Magdi Yacoub - Egypttoday

A new research study from HTF MI with titleGlobal Autologous Stem Cell Based Therapies Market Size, Status and Forecast 2019-2025provides an in-depth assessment of the Autologous Stem Cell Based Therapies including key market trends, upcoming technologies, industry drivers, challenges, regulatory policies, key players company profiles and strategies. The research study provides forecasts forAutologous Stem Cell Based Therapiesinvestments till 2025.

If you are involved in the Autologous Stem Cell Based Therapies industry or intend to be, then this study will provide you comprehensive outlook. Its vital you keep your market knowledge up to date segmented by Neurodegenerative Disorders, Autoimmune Diseases & Cardiovascular Diseases, , Embryonic Stem Cell, Resident Cardiac Stem Cells & Umbilical Cord Blood Stem Cells and major players. If you have a different set of players/manufacturers according to geography or needs regional or country segmented reports we can provide customization according to your requirement.

Get Access to Sample Pages Instantly @:https://www.htfmarketreport.com/sample-report/1793089-global-autologous-stem-cell-based-therapies-market-3

This report focuses on the global Autologous Stem Cell Based Therapies status, future forecast, growth opportunity, key market and key players. The study objectives are to present the Autologous Stem Cell Based Therapies development in United States, Europe and China.

This study primarily helps understand which market segments or Region or Country they should focus in coming years to channelize their efforts and investments to maximize growth and profitability. These stakeholders include Autologous Stem Cell Based Therapies manufacturers such asRegeneus, Mesoblast, Pluristem Therapeutics Inc, U.S. STEM CELL, INC., Brainstorm Cell Therapeutics, Tigenix & Med cell Europe, etc.Primary sources are mainly industry experts from core and related industries, and manufacturers related to all segments of the industry supply chain. The bottom-up approach is being utilized to project themarket size of the Autologous Stem Cell Based Therapiesbased on end-user industry and region, in terms of value. With the help of data triangulation procedure and validation of data through primary interviews and expert calls helps cover primary market, along with individual market share & sizes are determined and confirmed with this study.

** The Values marked with XX is confidential data. To know more about CAGR figures fill in your information so that our business development executive can get in touch with you.

Global Autologous Stem Cell Based Therapies (Thousands Units) and Revenue (Million USD) Market Split by Product Type such as , Embryonic Stem Cell, Resident Cardiac Stem Cells & Umbilical Cord Blood Stem Cells

The research study is segmented by Application as well such as Neurodegenerative Disorders, Autoimmune Diseases & Cardiovascular Diseases with historical and projected market share and compounded annual growth rate.

Global Autologous Stem Cell Based Therapies Sales (Thousands Units) by Application (2017-2022)

(2017-2022)

Read Detailed Index of full Research Study at @https://www.htfmarketreport.com/reports/1793089-global-autologous-stem-cell-based-therapies-market-3

Key questions answered in this report Global Autologous Stem Cell Based Therapies Market Size, Status and Forecast 2019-2025

What will be the market size and the growth rate in 2025?What are the key factors driving the Global Autologous Stem Cell Based Therapies market?Who are the key market players and what are their strategies in the Global Autologous Stem Cell Based Therapies market?What are the key market trends impacting the growth of the Global Autologous Stem Cell Based Therapies market?What trends, challenges and barriers are influencing its growth?What are the market opportunities and threats faced by the vendors in the Global Autologous Stem Cell Based Therapies market?What are the key outcomes of the five forces analysis of the Autologous Stem Cell Based Therapies market?

Geographically, this report is segmented into several key Regions such as United States, Europe, China, Japan, Southeast Asia, India & Central & South America, with production, consumption, revenue (million USD), and market share and growth rate of Global Autologous Stem Cell Based Therapies in these regions, from 2014 to 2025 (forecast), covering

The report provides a basic overview of the Autologous Stem Cell Based Therapies industry including definitions, classifications, applications and industry chain structure. And development policies and plans are discussed as well as manufacturing processes and capital expenditures.Further it focuses on global major leading industry players with information such as company profiles, product picture and specifications, sales, market share and contact information. Whats more, the Autologous Stem Cell Based Therapies industry development trends and marketing channels are analyzed.The study is organized with the help of primary and secondary data collection including valuable information from key vendors and participants in the industry. It includes historical data from 2012 to 2017 and projected forecasts till 2022 which makes the research study a valuable resource for industry executives, marketing, sales and product managers, consultants, analysts, and other people looking for key industry related data in readily accessible documents with easy to analyze visuals, graphs and tables. The report answers future development trend of Autologous Stem Cell Based Therapies on the basis of stating current situation of the industry in 2017 to assist manufacturers and investment organization to better analyze the development course of Autologous Stem Cell Based Therapies Market.

Buy this research report @https://www.htfmarketreport.com/buy-now?format=1&report=1793089

There are 15 Chapters to display the Global Autologous Stem Cell Based Therapies market.

Chapter 1, to describe Definition, Specifications and Classification of Autologous Stem Cell Based Therapies, Applications of Autologous Stem Cell Based Therapies, Market Segment by Regions;Chapter 2, to analyze the Manufacturing Cost Structure, Raw Material and Suppliers, Manufacturing Process, Industry Chain Structure;Chapter 3, to display the Technical Data and Manufacturing Plants Analysis of Autologous Stem Cell Based Therapies, Capacity and Commercial Production Date, Manufacturing Plants Distribution, R&D Status and Technology Source, Raw Materials Sources Analysis;Chapter 4, to show the Overall Market Analysis, Capacity Analysis (Company Segment), Sales Analysis (Company Segment), Sales Price Analysis (Company Segment);Chapter 5 and 6, to show the Regional Market Analysis that includes United States, Europe, China, Japan, Southeast Asia, India & Central & South America, Autologous Stem Cell Based Therapies Segment Market Analysis (by Type);Chapter 7 and 8, to analyze the Autologous Stem Cell Based Therapies Segment Market Analysis (by Application) Major Manufacturers Analysis of Autologous Stem Cell Based Therapies;Chapter 9, Market Trend Analysis, Regional Market Trend, Market Trend by Product Type [, Embryonic Stem Cell, Resident Cardiac Stem Cells & Umbilical Cord Blood Stem Cells], Market Trend by Application [Neurodegenerative Disorders, Autoimmune Diseases & Cardiovascular Diseases];Chapter 10, Regional Marketing Type Analysis, International Trade Type Analysis, Supply Chain Analysis;Chapter 11, to analyze the Consumers Analysis of Autologous Stem Cell Based Therapies;Chapter 12, to describe Autologous Stem Cell Based Therapies Research Findings and Conclusion, Appendix, methodology and data source;Chapter 13, 14 and 15, to describe Autologous Stem Cell Based Therapies sales channel, distributors, traders, dealers, Research Findings and Conclusion, appendix and data source.

Enquire for customization in Report @https://www.htfmarketreport.com/enquiry-before-buy/1793089-global-autologous-stem-cell-based-therapies-market-3

Check for discount @https://www.htfmarketreport.com/request-discount/1793089-global-autologous-stem-cell-based-therapies-market-3

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Europe or Asia.

About Author:HTF Market Report is a wholly owned brand of HTF market Intelligence Consulting Private Limited. HTF Market Report global research and market intelligence consulting organization is uniquely positioned to not only identify growth opportunities but to also empower and inspire you to create visionary growth strategies for futures, enabled by our extraordinary depth and breadth of thought leadership, research, tools, events and experience that assist you for making goals into a reality. Our understanding of the interplay between industry convergence, Mega Trends, technologies and market trends provides our clients with new business models and expansion opportunities. We are focused on identifying the Accurate Forecast in every industry we cover so our clients can reap the benefits of being early market entrants and can accomplish their Goals & Objectives.

Contact US :Craig Francis (PR & Marketing Manager)HTF Market Intelligence Consulting Private LimitedUnit No. 429, Parsonage Road Edison, NJNew Jersey USA 08837Phone: +1 (206) 317 1218sales@htfmarketreport.com

Read the rest here:
Autologous Stem Cell Based Therapies Market Report with Depth Analysis 2019 | Regeneus, Mesoblast - Tech Platform

Overview of current stem cell-based approaches to treat heart disease

Since heart failure after heart attacks results from death of heart muscle cells, researchers have been developing strategies to remuscularize the damaged heart wall in efforts to improve its function. Researchers are transplanting different types of stem cell and progenitor cells (see above) into patients to repair the damaged heart muscle. These strategies have mainly used either adult stem cells (found in bone marrow, fat, or the heart itself) or pluripotent (ES or iPS) cells.

Preliminary results from experiments with adult stem cells showed that they appeared to improve cardiac function even though they died shortly after transplantation. This led to the idea that these cells can release signals that can improve function without replacing the lost muscle. Clinical trials began in the early 2000s transplanting adult stem cells from the bone marrow and then from the heart. These trials demonstrated that transplanting cells into damaged hearts is feasible and generally safe for patients. However, larger trials that were randomized, blinded, and placebo-controlled, showed fewer indications of improved function. The consensus now is that adult stem cells have modest, if any, benefit to cardiac function.

Research shows that pluripotent stem cell-derived cardiomyocytes can form beating human heart muscle cells that both release the necessary signals and replace muscle lost to heart attack. Transplantation of pluripotent stem cell-derived cardiac cells have demonstrated substantial benefits to cardiac function in animal models of heart disease, from mice to monkeys. Recently, pluripotent stem cell-derived interventions were used in clinical trials for the first time. Patches of human heart muscle cells derived from the stem cells were transplanted onto the surface of failing hearts. Early results suggest that this approach is feasible and safe, but it is too early to know whether there are functional benefits.Research is ongoing to test cellular therapies to treat heart attacks by combining different types of stem cells, repeating transplantations, or improving stem cell patches. Clinical trials using these improved methods are currently targeted to begin around 2020.Unfortunately, many unscrupulous clinics are making unsubstantiated claims about the efficacy of stem cell therapies for heart failure, creating confusion about the current state of cellular approaches for heart failure. To learn more about warning signs of these unproven interventions, please visit Nine Things to Know About Stem Cell Treatments.

More here:
Heart Disease A Closer Look at Stem Cells

How do Stem Cellsfunction?Stem cells have the capacity to migrate to injured tissues, a phenomenon calledhoming. This occurs by injury or disease signals that are released from the distressed cells and tissue. Once stem cells arrive,they dock on adjacent cells to commence performing their job to repair the problem.

Stem cells serve as a cell replacementwhere they change into the required cell type such as a muscle cell, bone orcartilage. This is ideal for traumaticinjuries and many orthopedic indications.

They do not express specific human leukocyte antigens (HLAs) which helpthem avoid the immune system. Stemcells dock on adjacent cells and release proteins called growth factors, cytokines and chemokines. These factors help control many aspects of the healing and repairprocess systemically.

Stem cells control the immune system and regulate inflammation which is a keymediator of disease, aging, and is ahallmark of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.

They help to increase new blood vesselformation so that tissues receive proper blood flow and the correct nutrients needed to heal as in stroke, peripheral arterydisease and heart disease.

Stem cells provide trophic support forsurrounding tissues and help hostendogenous repair. This works wellwhen used for orthopedics. In case ofdiabetes, it may help the remaining beta cells in the pancreas to reproduce orfunction optimally.

As CSN research evolves, the field ofregenerative medicine and stem cells offers the greatest hope for those suffering from degenerative diseases, conditions for which there is currently no effective treatment or conditions that have failed conventional medical therapy.

Stem cell treatment is a complex process allowing us to harvest the bodys own repair mechanism to fight against degeneration, inflammation and general tissue damage. Stem cells are cells that can differentiate into other types of tissue to restore function and reduce pain.

Adult stem cells are found in abundance in adipose (fat) tissue, where more than 5million stem cells reside in every gram. These stem cells are called adult mesenchymal stem cells.

Our medical doctors extract stromal vascular fraction (SVF) from your own body to provide treatment using your very own cells. This process is calledautologous mesenchymal stem celltherapy. Our multi-specialty team deploys SVF under an institutional review board (IRB). This is an approved protocol that governs investigational work and the focus is to maintain safety of autologous use of SVF for various degenerative conditions.

How do we perform the stem cell treatment?Our procedure is very safe and completed in a single visit to our clinic. On the day of treatment, our physicians inject a localanaesthetic and harvest approximately 60 cc (2 oz.) of stromalvascular fraction (SVF) from under the skin of your flanks or abdomen. The extracted SVF is then refined in a closed system using strictCSN protocols to produce pure stromalvascular fraction (SVF). SVF containsregenerative cells including mesenchymal and hematopoietic stem cells, macrophages, endothelial cells, immune regulatory cells, and important growth factors that facilitate your stem cell activity. CSN technology allows us to isolate high numbers of viable stem cells that we can immediately deploy directly into a joint, trigger point, and/or byintravascular infusion. Specific deployment methods have been developed that are unique for each condition being treated.

During the refinement process, thesubcutaneous harvested cells andtheir connecting collagen matrix willbe separated, leaving purified free stem cells. About half of the SVF will be pure stem cells, while the remainder will be acombination of other regenerative cellsand growth factors. Before the SVF isre-injected into your body during the final part of the process we perform a qualityand quantity test which will examine the cell count and viability.

Perfecting the stem cell treatmentOur team records cell numbers and viability so that we can gain a better understanding of what constitutes a successful treatment. Although it is not yet possible to predict what number of cells that will be recovered in a harvest, it is very important that we know the total cell count and cell viability. It is only with this data that we will beginto understand why treatments are verysuccessful, only slightly successful orunsuccessful.

While vigilant about patient safety, we are also learning and sharing with the CSN data bank about which diseases respond best and which deployment methods are most effective with over 80 other clinics.

This data collection from all over the world makes the Cell Surgical Network the worlds largest regenerative medicineclinical research organization.

Network physicians have the opportunity to share their data, as well as their clinical experiences, thus helping one anotherto achieve higher levels of scientificunderstanding and optimizing medical protocols.

Injecting into thevascular system and/ora jointWe will administer the stem cell treatment with two methods:

The belief is that for many degenerative joint conditions IV and intra-articulardeployment is superior because each of these conditions have a local pathology and a central pathology. The local resident stem cell population has been working very hard to repair the damage and over the course of time these stem cells have become worn out, depleted and slowly die. This essentially causes a state of stem cell depletion. When we inject our mix of stem cells, cytokines and growth factors (known as SVF)inflammation is decreased and theregenerative process improved.

The stem cells that we have injected will then bring the level of stem cells closer to the normal level, thus restoring the natural balance and allow the body to heal itself.

Caplan et al, The MSC: An Injury Drugstore, DOI 10.1016/j .stem.2011.06.008

How long does it last?Many studies have shown the healing and regenerative ability of stem cells. Forexample, a study in World Journal of Plastic Surgery (Volume 5[2]; May 2016) followed a woman with knee arthritis. Before and after analysis of MRI images confirmed new growth of cartilage tissue. Unlike steroids, lubricants, and other injectable treatments, stem cells actually repair damaged tissue.

As published in Experimental andTherapeutic Medicine (Volume 12[2]; August 2016), numerous studies with hundreds of patients showed continuous improvement of arthritis for two years. Patients showed improvement three months after a single treatment and they continued to show improvement for two full years. This is why stem cells are often referred to as regenerative medicine.

No one can guarantee results for this or any other treatment. Outcomes will vary from patient to patient. Each potential patient must be assessed individually to determine the potential for optimum results from this regenerative therapy. To learn more about stem cell therapy, please contact us by clicking here or calling our clinic at 604-708-CELL (604-708-2355).

Like Loading...

Read the original here:
Vancouver Stem Cell Treatment Centre | Stem Cells

There are many ways in which human stem cells can be used in research and the clinic. Studies of human embryonic stem cells will yield information about the complex events that occur during human development. A primary goal of this work is to identify how undifferentiated stem cells become the differentiated cells that form the tissues and organs. Scientists know that turning genes on and off is central to this process. Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A more complete understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy. Predictably controlling cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. While recent developments with iPS cells suggest some of the specific factors that may be involved, techniques must be devised to introduce these factors safely into the cells and control the processes that are induced by these factors.

Human stem cells are currently being used to test new drugs. New medications are tested for safety on differentiated cells generated from human pluripotent cell lines. Other kinds of cell lines have a long history of being used in this way. Cancer cell lines, for example, are used to screen potential anti-tumor drugs. The availability of pluripotent stem cells would allow drug testing in a wider range of cell types. However, to screen drugs effectively, the conditions must be identical when comparing different drugs. Therefore, scientists must be able to precisely control the differentiation of stem cells into the specific cell type on which drugs will be tested. For some cell types and tissues, current knowledge of the signals controlling differentiation falls short of being able to mimic these conditions precisely to generate pure populations of differentiated cells for each drug being tested.

Perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies. Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including maculardegeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.

Figure 3. Strategies to repair heart muscle with adult stem cells. Click here for larger image.

2008 Terese Winslow

For example, it may become possible to generate healthy heart muscle cells in the laboratory and then transplant those cells into patients with chronic heart disease. Preliminary research in mice and other animals indicates that bone marrow stromal cells, transplanted into a damaged heart, can have beneficial effects. Whether these cells can generate heart muscle cells or stimulate the growth of new blood vessels that repopulate the heart tissue, or help via some other mechanism is actively under investigation. For example, injected cells may accomplish repair by secreting growth factors, rather than actually incorporating into the heart. Promising results from animal studies have served as the basis for a small number of exploratory studies in humans (for discussion, see call-out box, "Can Stem Cells Mend a Broken Heart?"). Other recent studies in cell culture systems indicate that it may be possible to direct the differentiation of embryonic stem cells or adult bone marrow cells into heart muscle cells (Figure 3).

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease, stroke, and congestive heart failure, has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic. Nearly 2,600 Americans die of CVD each day, roughly one person every 34 seconds. Given the aging of the population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes, CVD will be a significant health concern well into the 21st century.

Cardiovascular disease can deprive heart tissue of oxygen, thereby killing cardiac muscle cells (cardiomyocytes). This loss triggers a cascade of detrimental events, including formation of scar tissue, an overload of blood flow and pressure capacity, the overstretching of viable cardiac cells attempting to sustain cardiac output, leading to heart failure, and eventual death. Restoring damaged heart muscle tissue, through repair or regeneration, is therefore a potentially new strategy to treat heart failure.

The use of embryonic and adult-derived stem cells for cardiac repair is an active area of research. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells including mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated as possible sources for regenerating damaged heart tissue. All have been explored in mouse or rat models, and some have been tested in larger animal models, such as pigs.

A few small studies have also been carried out in humans, usually in patients who are undergoing open-heart surgery. Several of these have demonstrated that stem cells that are injected into the circulation or directly into the injured heart tissue appear to improve cardiac function and/or induce the formation of new capillaries. The mechanism for this repair remains controversial, and the stem cells likely regenerate heart tissue through several pathways. However, the stem cell populations that have been tested in these experiments vary widely, as do the conditions of their purification and application. Although much more research is needed to assess the safety and improve the efficacy of this approach, these preliminary clinical experiments show how stem cells may one day be used to repair damaged heart tissue, thereby reducing the burden of cardiovascular disease.

In people who suffer from type1 diabetes, the cells of the pancreas that normally produce insulin are destroyed by the patient's own immune system. New studies indicate that it may be possible to direct the differentiation of human embryonic stem cells in cell culture to form insulin-producing cells that eventually could be used in transplantation therapy for persons with diabetes.

To realize the promise of novel cell-based therapies for such pervasive and debilitating diseases, scientists must be able to manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment. The following is a list of steps in successful cell-based treatments that scientists will have to learn to control to bring such treatments to the clinic. To be useful for transplant purposes, stem cells must be reproducibly made to:

Also, to avoid the problem of immune rejection, scientists are experimenting with different research strategies to generate tissues that will not be rejected.

To summarize, stem cells offer exciting promise for future therapies, but significant technical hurdles remain that will only be overcome through years of intensive research.

Previous|VII. What are the potential uses of human stem cells and the obstacles that must be overcome before these potential uses will be realized?|Next

Original post:
Stem Cell Basics VII. | stemcells.nih.gov

Adult stem cells are the bodys toolbox, called into action by normal wear and tear on the body, and when serious damage or disease attack. Researchers believe that adult stem cells also have the potential, as yet untapped, to be tools in medicine. Scientists and physicians are working towards being able to treat patients with their own stem cells, or with banked donor stem cells that match them genetically.

Grown in large enough numbers in the lab, then transplanted into the patient, these cells could repair an injury or counter a diseaseproviding more insulin-producing cells for people with type 1 diabetes, for example, or cardiac muscle cells to help people recover from a heart attack. This approach is called regenerative medicine.

A number of challenges must be overcome before the full therapeutic potential of adult stem cells can be realized. Scientists are exploring practical ways of harvesting and maintaining most types of adult stem cells. Right now, scientists do not have the ability to grow the cells in the amounts needed for treatment. More work is also needed to find practical ways to direct the different kinds of cells to where theyre needed in the body, preferably without the need for surgery or other invasive methods.

Research in all aspects of adult stem cells and their potential is underway at Childrens Hospital Boston. Realizing that potential will require years of research, but promising strides are being made.

Read this article:
Why are Adult Stem Cells Important? Boston Children's ...

By: Ian Murnaghan BSc (hons), MSc - Updated: 12 Sep 2015| *Discuss

One of the biggest hurdles in stem cell research involves the use of embryonic stem cells. While these stem cells have the greatest potential in terms of their ability to differentiate into many different kinds of cells in the human body, they also bring with them enormous ethical controversies. The extraction of embryonic stem cells involves the destruction of an embryo, which upsets and outrages some policy makers and researchers as well as a number of public members. Not only that, but actually obtaining them is a challenge in itself and one that has become more difficult in places such as the United States, where policies have limited the availability of embryonic stem cells for use.

Although researchers have focused on harnessing the power of adult stem cells, there have still been many difficulties in the practical aspects of these potential therapies. In an ideal world, we would be able to use embryonic stem cells without destroying an embyro. Now, however, this ideal hope may actually have some realistic basis. In recent medical news, there has been important progress in the use of embryonic stem cells.

There are still many more tests and research that must be conducted to verify the safety and reliability of the procedure but it is indeed hopeful that funding can now increase for stem cell research. If you are an avid reader of health articles, you will probably be able to stay up-to-date on the latest developments related to this medical news. This newest research into embryonic stem cells holds promise and hope for appeasing the controversy around embryonic stem cell use and allowing for research to finally move forward with fewer challenges and controversies. For those who suffer from one of the many debilitating diseases and conditions that stem cell treatments may help or perhaps cure one day, this is welcome news.

You might also like...

Share Your Story, Join the Discussion or Seek Advice..

Time for Change - 12-Sep-15 @ 12:54 PM

Ellie - 25-Apr-14 @ 6:02 PM

Title:

(never shown)

Excerpt from:
Creating Embryonic Stem Cells Without Embryo Destruction

Cardiovascular disease, also called heart disease, is a broad medical term used to describe a group of conditions that affect the blood vessels or the heart. It is the most common cause of death worldwide.1

Conditions of cardiovascular disease include:

The Stem Cells Transplant Institutein Costa Rica, uses adult autologous stem cells for the treatment of cardiovascular disease (heart disease). The symptoms of cardiovascular disease will depend on the specific type of heart disease.

Treatment at the Stem Cells Transplant Institute could help improve the symptoms of cardiovascular disease such as:

Heart disease and cardiovascular disease are often used interchangeably. These terms refer to a group of conditions that affect the blood vessels and heart. Valvular heart disease affects how the valves pump blood flow in and out of the heart. Cardiomyopathy affects the contractions of the heart muscle. Heart arrhythmias are disturbances in the electrical conduction making the heart beat irregular. Coronary artery disease is the most common cause of cardiovascular disease and stem cell therapy may be an effective treatment.

Coronary artery disease is caused by atherosclerosis, the buildup of plaque, causing a narrowing or blocking the blood vessels in the coronary arteries. Coronary artery disease is the leading cause of cardiovascular disease. Atherosclerosis can lead to chest pain, heart attack or stroke.

Coronary arteries carry oxygen rich blood to the heart. Plaque is caused by the presence of cholesterol, calcium, fat, and other substances in the blood. When plaque builds up in the blood vessels it narrows the arteries causing them to harden and weaken, reducing the amount of oxygen rich blood to the heart. As a result, the heart cannot pump blood effectively to the rest of the body potentially leading to heart failure and ultimately death.

If the plaque building up in the coronary arteries breaks, a blood clot forms around the plaque. If the clot cuts off the blood flow to the heart muscle completely, the heart muscle is unable to get the necessary oxygen and nutrients causing a part of the heart muscle to die. The result is a heart attack or myocardial infarction,

Coronary artery disease, high blood pressure or a previous heart attack can lead to the onset of heart failure. Heart failure is a chronic, progressive disease typically caused by another heart condition resulting in the heart muscle losing its ability to supply the rest of body with enough blood and oxygen.

Atherosclerosis can also cause peripheral artery disease. Peripheral arterial disease occurs when the narrowed peripheral arteries cannot send enough blood flow to the extremities, usually the legs. The most common symptoms of peripheral artery disease are; cramping, pain, and/or tiredness in the leg or hip muscles during exertion. The most severe symptom of peripheral artery disease is critical limb ischemia, pain at rest due to reduced blood flow to the limb.

Approximately 85% of strokes are ischemic strokes. Atherosclerosis is the most common cause of ischemic stroke. If the arteries become too narrow due to plaque buildup, the blood cells may collect and form a clot. A larger clot can block the artery where it is formed (thrombotic stroke) while a smaller clot may travel until it reaches an artery closer to the brain (embolic stroke). When the arteries to your brain become narrow or blocked, the required blood flow is reduced resulting in stroke. Other causes of ischemic stroke are clots due to an irregular heartbeat or heart attack.

Stem cell therapy at the Stem Cells Transplant Institute may be a good alternative for patients seeking a safe, non-surgical treatment for cardiovascular disease.

Notably, adult stem and progenitor cells including.mesenchymal stem cells have progressed into clinical trials and have shown positive benefits.5

Stem cell transplantation uses healthy cells to promote the repair of damaged cells and regeneration of healthy and functional cells to repair injured tissue.1 The therapeutic effect of stem cell transplantation in patients with cardiovascular disease may be due to the paracrine effect. The theory is transplanted stem cells repair damaged tissue by releasing factors that promote regeneration of healthy stem cells, reduce inflammation, promote the growth of new blood vessels, inhibit cell death, and reduce hypertrophy.1

The results of initial research using mesenchymal stem cell transplantation:

Heart Failure

Adipose derived stem cells improve left ventricular function, promote angiogenesis, lower fibrosis, and decrease inflammation. Several months following treatment, stem cells continue to migrate to the heart muscle regenerating and renewing healthy heart function. Stem cell therapy cannot help all patients with cardiovascular disease but for many patients stem cell therapy combined with lifestyle modification may be a safe, effective, non-surgical alternative treatment.

Lifestyle changes that can help improve cardiovascular disease include:

The Stem Cells Transplant Institute uses autologous mesenchymal stem cells for the treatment of cardiovascular disease. Autologous means the stem cells are collected from the recipient so the risk of rejection is virtually eliminated. Mesenchymal stem cells are one type of adult stem cells that are found in a variety of tissues including; adipose tissue, lung, bone marrow, and blood. Mesenchymal stem cells have several advantages over other types of stem cells; ability to migrate to sites of tissue injury, strong immunosuppressive effect, and better safety after infusion.2,3 Mesenchymal stem cells are a promising treatment for cardiovascular disease. Treatment at the Stem Cells Transplant Institute may improve the symptoms and long-term complications of cardiovascular disease.

A team of stem cell experts developed an FDA approved method and protocol for harvesting and isolating adipose derived stem cells for autologous reimplantation. The collection and use of adult stem cells does not require the destruction of embryos and for this reason, more U.S. federal funding is being spent on stem cell research.

The stem cells are administered intravenously.

Costa Rica has one of the best healthcare systems in world and is ranked among the highest for medical tourism. Using the most advanced technologies, the team of experts at The Stem Cells Transplant Institute believes in the potential of stem cell therapy for the treatment of cardiovascular disease. We are committed to providing personalized service and the highest quality of care to every patient. Contact us to see if stem cell therapy may be a treatment option for you.

1.Sun R.Advances in stem cell therapy for cardiovascular disease (Review). National Journal of Mol. Med. 38: 23-29, 2016. 2 Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, et al: Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308: 2369-2379, 2012.3 Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, et al: Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 12: 459-465, 2006. 4 Mazo M, Planat-Bnard V, Abizanda G, Pelacho B, Lobon B, Gavira JJ, Peuelas I, Cemborain A, Pnicaud L, Laharrague P, et al: Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail 10: 454-462, 2008. 5 Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease Luqia Hou,1,2 Am J Physiol Heart Circ Physiol 310: H455H465, 2016. 6 Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94: 678685, 2004. 7 Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109: 15431549, 2004.

8 Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrowderived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308: 23692379, 2012.

Go here to see the original:
Stem Cell Treatment Cardiovascular Disease, Heart Disease ...

Stem cells in menstrual blood have similar regenerative capabilities as thestem cells in umbilical cord blood and bone marrow. Cryo-Cell's patent-pendingmenstrual stem cell service offers women in their reproductive years the ability to store and preserve these cells for potential use by herself or a family memberfree from ethical or political controversy.

Cryo-Cell is the only stem cell bank in the world that can offer womenthe reassurance and peace of mind that comes with this opportunity.

What are menstrual stem cells?Stem cells in menstrual blood are highly proliferativeandpossess the unique ability to develop into various other types of healthy cells. During a womans menstrual cycle, these valuable stem cells are discarded.

Cryo-Cell'smenstrual stem cell bankingservice captures those self-renewing stem cells, processes and cryopreserves them for emerging cellular therapies that hold the promise of potentially treatinglife-threatening diseases.

How are menstrual stem cells collected, processed and stored?The menstrual blood is collected in a physicians officeusing a medical-grade silicone cup in place of a tampon orsanitary napkin. The sample is shipped to Cryo-Cell via a medical courier and processed in our state-of-the-art ISO Class 7 clean room.

The menstrual stem cells are stored in two cryovials that are overwrapped to safeguard them during storage. The overwrapped vials are cryogenically preserved in a facility that isclosely monitored at all times to ensure that your menstrual stem cells are safe and ready for future use.

What are the benefits of banking menstrual stem cells?Cryo-Cell's innovative menstrual stem cell banking service provides women with the exclusive opportunity to build their own personal healthcare portfolio with stem cells that will be a 100% match for the donor. Menstrual stem cells have demonstrated the capability of differentiating into many other types of stem cells such as cardiac, neural, bone, fat and cartilage.

Bankingmenstrual stem cells now is an investment in your future medical needs. Currently, they are being studied to treat stroke, heart disease, diabetes, neurodegenerative disease, and ischemic wounds in pre-clinical and clinical models.

Cryo-Cells activities for New York State residents are limited to collection, processing, and long-term storage ofmenstrual stem cells. Cryo-Cells possession of a New York State license for such collection, processing, and long-term storage does not indicate approval or endorsement of possible future uses or future suitability of these cells.

See original here:
Banking Menstrual Stem Cells | What are Menstrual Stem ...

Stem cells are incredible. Science is only starting to scratch the surface of how these amazing cells can help people suffering from heart failure and other cardiovascular issues. Heres some information on what stem cells are, and how they may help heart attack patients and others who have problems involving their heart tissue.

There are more than 200 kinds of cells in the body, and each type is specifically structured for the job its supposed to do. There are skin cells, nerve cells, and cells that form heart tissue and other tissues in the body.1

Theyre found in bone marrow, blood vessels, the liver, the brain, and other parts of the body. Stem cells are even found in the umbilical cord. These sophisticated cells change over time as the body matures. Some of them disappear shortly after youre born, while others stay with you for a lifetime.2

There are three main types of stem cells tissue-specific (adult stem cells), embryonic stem cells, and induced pluripotent (iPS) stem cells. Heres a quick look at each type:

These typically reside in a specific organ, generating other cells to support the health of that organ. They replace those that are lost through injury, or through everyday living.3

Embryonic stem cells form about three to five days after a sperm fertilizes an egg. These are also known as pluripotent cells. This simply means they can develop into any sort of cell the body needs to develop.4

Embryonic cells have been the source of a massive controversy. The main reason is that harvesting these cells destroys the embryo.5 Scientists are working to develop iPS cells that come from adult stems cells rather than embryonic cells. Early research indicates that these cells may share many of the same characteristics of embryonic cells. But there are differences between the two, and there is more work to be done before scientists know exactly what those differences are.6

Research is ongoing into the potential use of stem cells for heart health. For example, work is being done to see if stem cells can help improve heart attack survival rates. Scientists are also looking into the potential for giving a patient their own cardiac stem cells after a heart attack, or even giving patients non-cardiac stem cells from a donor after an attack takes place.7

The goal of this research is to eventually provide cardiac patients with stem cells that can regenerate heart tissue that has been damaged. Some researchers feel that these advances are imminent, while others believe there is a great deal of work yet to be done.8

Early results from ongoing clinical trials involving stem cells for heart health are extremely promising. In one study, a group of 109 patients suffering from heart failure received either stem cell therapy or a placebo. According to the results, the patients who received stem cells were at significantly lower risk of hospitalization or death due to a sudden worsening of their condition.9

Heart failure affects more than 5 million people in the U.S.10 It occurs when the heart gradually weakens to the point to where it cant pump enough blood to meet the needs of the rest of the body. For those with severe heart failure, the only options are either to have a heart transplant or have a device planted to help the heart continue pumping. And even this is only a temporary measure theyll still need a transplant.11

Another study involved the use of stem cells from the umbilical cord. This trial involved 30 heart failure patients. Like the previous study, one group received stem cells while the other received a placebo. The umbilical cords were donated by healthy mothers whose babies were delivered through cesarean section.12

According to the results, the hearts of patients who received the umbilical cord stem cells pumped better than those of the placebo group. The stem cell patients also showed improved quality of life and day-to-day functioning. In addition, the stem cell group did not report any adverse effects, such as immune system reactions.13

As you can see, the use of stem cells to treat heart patients shows great promise. But this is still an extremely young scientific field, and a great deal more research must be performed. Many questions have to be answered, such as what approaches to stem cell harvesting will work the best and what types of side effects are possible from stem cell treatment.

However, this research does bring hope. And hope is something that is incredibly important to many of those suffering from severe cardiac illnesses.

Learn More:How Cardio Can Change Your Brain (And Why Thats Good News!)NEWS: A Vaccine For Arthritis Is Closer Than You ThinkAre Organ Donors At Risk of Becoming Obsolete?

Sources1.https://askabiologist.asu.edu/questions/human-cell-types2.https://www.medicalnewstoday.com/info/stem_cell3.http://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells4.https://stemcells.nih.gov/info/basics/3.htm5.http://www.cnn.com/2013/07/05/health/stem-cells-fast-facts/index.html6.http://www.closerlookatstemcells.org/learn-about-stem-cells/types-of-stem-cells#induced-pluripotent7.https://my.clevelandclinic.org/health/diseases/17508-stem-cell-therapy-for-heart-disease8.https://www.health.harvard.edu/heart-health/repairing-the-heart-with-stem-cells9.https://www.ncbi.nlm.nih.gov/pubmed/2705988710.https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm11.http://www.heart.org/HEARTORG/Conditions/HeartFailure/TreatmentOptionsForHeartFailure/Devices-and-Surgical-Procedures-to-Treat-Heart-Failure_UCM_306354_Article.jsp#.WleO-yMrJ3k12.https://www.medicalnewstoday.com/articles/319552.php13.http://circres.ahajournals.org/content/early/2017/09/15/CIRCRESAHA.117.310712

Read the original post:
Stem Cells For Heart Health: What The Current Research ...

Bellin, M., Marchetto, M. C., Gage, F. H. & Mummery, C. L. Induced pluripotent stem cells: the new patient? Nat. Rev. Mol. Cell Biol. 13, 713726 (2012).

Matsa, E., Burridge, P. W. & Wu, J. C. Human stem cells for modeling heart disease and for drug discovery. Sci. Transl. Med. 6, 239 (2014).

Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616623 (2014).

Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230234 (2011).

Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511523 (2014).

Feric, N. T. & Radisic, M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv. Drug Deliv. Rev. 96, 110134 (2016).

Domian, I. J. et al. Generation of functional ventricular heart muscle from mouse ventricular progenitor cells. Science 326, 426429 (2009).

Lundy, S. D., Zhu, W. Z., Regnier, M. & Laflamme, M. A. Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cells Dev. 22, 19912002 (2013).

Nunes, S. S. et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat. Methods 10, 781787 (2013).

Mannhardt, I. et al. Human engineered heart tissue: analysis of contractile force. Stem Cell Reports 7, 2942 (2016).

Ribeiro, M. C. et al. Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitrocorrelation between contraction force and electrophysiology. Biomaterials 51, 138150 (2015).

Shadrin, I. Y. et al. Cardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues. Nat. Commun. 8, 1825 (2017).

Brette, F. & Orchard, C. T-tubule function in mammalian cardiac myocytes. Circ. Res. 92, 11821192 (2003).

Wiegerinck, R. F. et al. Force frequency relationship of the human ventricle increases during early postnatal development. Pediatr. Res. 65, 414419 (2009).

Lopaschuk, G. D. & Jaswal, J. S. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J. Cardiovasc. Pharmacol. 56, 130140 (2010).

Jackman, C. P., Carlson, A. L. & Bursac, N. Dynamic culture yields engineered myocardium with near-adult functional output. Biomaterials 111, 6679 (2016).

Radisic, M. et al. Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds. Proc. Natl Acad. Sci. USA 101, 1812918134 (2004).

Eng, G. et al. Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes. Nat. Commun. 7, 10312 (2016).

Hasenfuss, G. et al. Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species. Circ. Res. 68, 836846 (1991).

Chung, S. et al. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat. Clin. Pract. Cardiovasc. Med. 4, S60S67 (2007).

Gong, G. et al. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350, aad2459 (2015).

Porter, G. A. Jr et al. Bioenergetics, mitochondria, and cardiac myocyte differentiation. Prog. Pediatr. Cardiol. 31, 7581 (2011).

Vega, R. B., Horton, J. L. & Kelly, D. P. Maintaining ancient organelles: mitochondrial biogenesis and maturation. Circ. Res. 116, 18201834 (2015).

Gottlieb, R. A. & Bernstein, D. Metabolism. Mitochondria shape cardiac metabolism. Science 350, 11621163 (2015).

Sun, R., Bouchard, M. B. & Hillman, E. M. C. SPLASSH: Open source software for camera-based high-speed, multispectral in-vivo optical image acquisition. Biomed. Opt. Express 1, 385397 (2010).

Hong, T. et al. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat. Med. 20, 624632 (2014).

Bers, D. M. Cardiac excitationcontraction coupling. Nature 415, 198205 (2002).

Huebsch, N. et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep. 6, 24726 (2016).

Tulloch, N. L. et al. Growth of engineered human myocardium with mechanical loading and vascular coculture. Circ. Res. 109, 4759 (2011).

Ma, J. et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am. J. Physiol. Heart Circ. Physiol. 301, H2006H2017 (2011).

Morikawa, K., Song, L., Ronaldson-Bouchard, K., Vunjak-Novakovic, G. & Yazawa, M. Electrophysiological recordings of cardiomyocytes isolated from engineered human cardiac tissues derived from pluripotent stem cells.Protoc. Exch. https://doi.org/10.1038/protex.2018.030 (2018).

Continued here:
Advanced maturation of human cardiac tissue grown from ...

To determine why the first stem cell trials were not providing the anticipated therapeutic potential, all variables, such as which stem cells were used, and how they were developed and administered, were open to consideration, says Dr. Epstein.

A key issue was the use of autologous stem cells in all previous studies. Studies demonstrated these old stem cells are functionally defective when compared to stem cells obtained from young healthy individuals. So harvesting a healthy young donors bone marrow and growing the resident stem cells might produce more robust cells.

However, giving a patient allogenic stem cells raised an important issue: whether such cells will be rejected by an immune response. But research showed mesenchymal stem cells (MSCs), a type of adult stem cell, have been designed by nature to be stealth bombers, explainsDr. Epstein. They express molecules on their surface that prevent the body from recognizing the cells as foreign, so the patient does not reject the donated MSCs.

To further explore and refine potential stem cell cardiovascular therapies, MHVI expanded the translational research team to include Michael Lipinski, MD, PhD, an expert in molecular biology and scientific lead for preclinical research at the MedStar Cardiovascular Research Network, and Dror Luger, PhD, an expert in immunology and inflammatory responses. By bringing together these diverse areas of expertise, we forged a team with the potential to produce research that could lead to important breakthroughs in understanding how stem cells might work and thereby provide more successful treatment of patients with cardiac disease, says Dr. Epstein.

CardioCell, a San Diego-based stem cell company focused on stem cell therapy for cardiovascular disease, found that MSCs grew faster and showed improved function when cultured in a reduced oxygen environment. Stem cells typically grow in the body, in bone marrow and other tissues, in a low oxygen environmentonly five percent oxygen, as opposed to room air, which is about 20 percent, explains Dr. Lipinski. All previous stem cell trials used cells exposed to, and grown under, room air oxygen conditions.

Using CardioCells low oxygen-grown MSCs, the MHVI scientists demonstrated biologically important effects occurred, even when the MSCs were administered intravenously. This mode of administration was previously rejected by scientists who thought cells would be trapped in the first capillary bed they traversedthe lungsand never reach the heart.

However, the MHVI team demonstrated a small percentage of these IV administered MSCs did reach the heart, where they could exert beneficial effects. The cells seek out inflamed cardiac tissue after a heart attack because they upregulate receptors that allow them to be attracted to and penetrate inflamed tissue in high numbers, says Dr. Luger.

The investigators also found the cells residing in other tissues could provide other benefits. It has been shown that a heart attack activates the immune and inflammatory systems, including those in the spleen, explains Dr. Luger. The systemic anti-inflammatory effects produced by MSCs in the spleen, lungs and other tissues caused by the molecules secreted by the MSCs could exert positive effects as well. Dr. Epstein added that such anti-inflammatory effects could also benefit the excessive inflammatory activities that exist in many heart failure patients.

For the clinical heart failure trial, MHVI is partnering with CardioCell, which will grow and provide stem cells already used in Phase I and 2a clinical trials and approved by the Food and Drug Administration.

As an extension of their stem cell work, the MHVI investigators are building on the fact that any beneficial effect of adult stem cells will not derive from their transformation into heart muscle, but rather from the molecules they secrete; these, in turn, stimulate pathways favoring tissue healing. The team is investigating the use of liposomes as therapeutic delivery vehicles for these secreted products, which include those with anti-inflammatory and angiogenesis activities.

If successful, using MSCs for anti-inflammatory and immune-modulatory effects could have implicationsfor many different diseases, including arthritis and autoimmune diseases like rheumatoid arthritis. Dr. Epstein cautions that a great deal of research is yet to be done before such applications can be routinely used to treat patients with these conditions. For now, they hope the current studies in heart failure patients will demonstrate effectiveness. If so, Dr. Epstein says, it changes the whole playing field for stem cells.

Go here to see the original:
Next Steps for Cardiac Stem Cells - MedStar Heart ...

Jeff Huffman, MD,is the Director of the Cardiac Psychiatry Research Program (CPRP), Director of Inpatient Psychiatry Research, and an Associate Professor of Psychiatry at Harvard Medical School. He currently serves as principal investigator for over ten projects, and has been awarded grants from the American Heart Association, American Diabetes Association, the Templeton Foundation, American Foundation for Suicide Prevention, and the National Institutes of Health (NHLBI and NIDDK). He has numerous peer-reviewed publications, including 100 first or senior author publications. He has mentored post doctoral psychology fellows, junior psychiatrist and psychologist faculty, medical students, psychiatry residents, research fellows, psychologists, social workers, and he received the 2015 Mass General Psychiatry Outstanding Research Mentor Award. His areas of interest include the impact of psychiatric illness on patients with cardiac disease, and the development and use of positive psychological interventions in a wide range of populations.

Christopher Celano, MD,is an attending psychiatrist at Mass General, an Assistant Professor in Psychiatry at Harvard Medical School, and the Associate Director of the CPRP. He is the recipient of a K23 career development award sponsored by the National Heart, Lung, and Blood Institute to develop a psychological intervention to improve health behaviors in patients with heart failure. He has published over 35 articles with the team, is an active co-investigator on several projects, and serves as the project director of health behavior trials in patients with coronary artery disease and diabetes. His areas of interest include the impact of depression and anxiety on cardiac health as well as the promotion of positive psychological states and health behaviors in patients with mental illness and cardiovascular disease.

Scott Beach, MD,is an Assistant Professor in Psychiatry at Harvard Medical School. He is Program Director for the Mass General/McLean Adult Psychiatry Residency and an attending psychiatrist on the consultation service at Mass General. He is currently PI of a study investigating neuroimaging and gene expression in patients with catatonia prior to and following lysis with lorazepam, and an active co-investigator on multiple projects. He has published over 50 book chapters and peer-reviewed articles on topics including QTc prolongation with psychotropic medications, catatonia, and deception syndromes.

James Januzzi, MD,is an Associate Professor of Medicine in the Division of Cardiology at Harvard Medical School, and the Director of the Cardiac Intensive Care Unit at Mass General. He is a well-established researcher at Mass General with over 300 peer-reviewed research publications, over 100 review articles and chapters, and has edited three text books. He is internationally known as an expert in the study of biomarkers in patients with heart failure and other cardiac illnesses, and has served as a section editor on the recent American College of Cardiology/American Heart Association clinical practice guidelines for heart failure, and was the lead for the heart failure section for the Universal Definition of Myocardial Infarction Global Task Force. He has served as the primary cardiologist on projects for the CPRP for the past nine years, including collaborative care depression and anxiety management trials in hospitalized cardiac patients, and studies of positive psychological states in persons with heart disease.

Laura Duque, MD, is a research fellow at the CPRP. Her areas of interest include Consultation Liaison Psychiatry, catatonia, and mood disorders. She is primarily interested in studying the relationship between mental health and chronic diseases. Currently, she is in charge of medical data collection and participant screening for a study on a collaborative care intervention for cardiac inpatients with psychiatric comorbidities, as well as for four positive psychology interventions for individuals with acute coronary syndrome, diabetes, heart failure, and metabolic syndrome. She graduated from Universidad de los Andes School of Medicine in Bogot, Colombia and intends to apply for residency training in psychiatry this upcoming year.

Perla M. Romero, MD is a research fellow at the CPRP. She was born and raised in Bogot, Colombia, where she also attended Universidad de los Andes School of Medicine. During her studies, she was involved in several research projects, including an original investigation analyzing the association between armed conflict, violence and mental health. Her main interests include human behavior, neuroscience and mental health. Perla's main goal is to pursue a psychiatry training in the US, and intends to pursue an academic career dedicated to this specialty.

Juan Pablo Ospina, MD, is a research fellow at the CPRP. He graduated from Universidad de los Andes school of Medicine in Bogot, Colombia. He is interested in the intersection of Neurology and Psychiatry and in studying mind-brain-body interactions. At the CPRP, he oversees subject screening and medical data collection for several randomized clinical trials studying the impact of positive psychology and blended care interventions in patients with medical conditions including acute coronary syndrome, heart failure, diabetes and multiple sclerosis. Likewise, he contributes to the presentation of study findings in publications and poster sessions. In the future, he intends to apply to Neurology residency training.

Franklin King, MD, is an attending psychiatrist at Mass General and an Instructor in Psychiatry at Harvard Medical School. He joined the CPRP in 2018, after completing a fellowship in consult-liaison psychiatry at Mass General in 2018 and residency at MGH/McLean in 2017, where he also served as consult-liaison chief resident during his fourth year. He graduated from UMass Medical School in 2013. His clinical interests include disorders at the intersection of medicine and psychiatry, the mind-body interface, and neuropsychiatry.

Carol Mastromauro, MSW, LICSW, is one of the interventionists for the CPRP. She is a clinical research social worker who has been with the team for seven years. Carol specializes in anxiety and depression treatment and positive psychology interventions for cardiac populations. She has administered interventions to more than 200 subjects during her time at the CPRP, and recruited and evaluated over 350 cardiac inpatients for the SUCCEED and MOSAIC studies. Prior to joining the CPRP, Carol worked in geriatric research on memory disorders as well as working with Huntingtons disease patients and their families.

Rachel Millstein, PhD, MHS, is a clinical psychologist at Mass General and Assistant in Psychiatry at Harvard Medical School. She is the recipient of a National Institutes of Health K23 award to develop a multilevel intervention to promote health behaviors among patients with metabolic syndrome. Her research focuses on chronic disease prevention and the intersection of emotions and health. Rachel has authored many peer-reviewed articles and book chapters in these fields. Her clinical interests include evidence-based therapies, positive psychology, and mindfulness techniques for improving mood, anxiety, and well-being.

Emily Feig, PhD, is a research and clinical postdoctoral psychology fellow in her second year with the CPRP. She completed her doctoral training in clinical psychology at Drexel University and her doctoral internship in Health Psychology at Rush University Medical Center. Emily is an interventionist on the BEHOLD study. Her research interests focus on understanding risk factors for obesity and eating disorders, as well as improving adherence to health behaviors in individuals with obesity-related chronic disease. Clinically, Emily specializes in cognitive behavioral and acceptance-based therapies targeting anxiety, depression, and disordered eating.

Christina Massey, PhD, is a clinical psychologist at Mass General and Instructor at Harvard Medical School in her first year with the CPRP. She completed her doctoral training in clinical psychology with a specialization in forensic psychology at The Graduate Center, CUNY at John Jay College of Criminal Justice and her doctoral internship at Mass General. Christina is currently an interventionist on the BEHOLD study. Her clinical and research interests include evidence-based treatments, diagnostic and forensic assessment and evaluation, and investigating the long-term consequences (including resilience) of childhood adversity.

Wei-Jean Chung, PhD, is a clinical psychologist at Mass General and Instructor at Harvard Medical School. She received her doctoral training in clinical psychology at Adelphi University prior to completing her doctoral internship and postdoctoral fellowship at Mass General. She is currently an interventionist for the PEACE and BEHOLD Studies at the CPRP. In addition to her involvement with the CPRP, her clinical practice involves caring for people with serious mental illness and complex personality organization across multiple clinical services within Mass General Psychiatry, including Primary Care Psychiatry, the Dialectical Behavioral Therapy Team, the Psychological Evaluation and Research Laboratory, and the Mass General inpatient psychiatry service.

Lydia Brown, PhD, is a psychologist and postdoctoral researcher with an interest in links between positive emotional/cognitive qualities and health. She completed her PhD and clinical training at The University of Melbourne, Australia, where she continues to hold a joint academic position. She has a particular interest in self-compassion, as well as novel interventions that might simultaneously boost both mental and physical health in the second half of life.

Margaret C. Bell, RN, MPH, MS, works as a nurse care manager in the CPRPs Total Health Study, a blended care intervention trial for patients with comorbid heart disease and mood or anxiety disorders. She is a registered nurse with a masters degree in psychiatric nursing from Boston College in 1994. Her work at Boston College included publications on Russian immigrant adjustment, effect of post-partum depression on mother-child interaction and domestic violence in pregnant women. She has worked in health care in Jerusalem, Amsterdam, New York, New Hampshire and Boston as a public health nurse, student health nurse, and psychiatric nurse. For the last 20 years she has monitored and managed NIH multi-site research trials in hepatology and cardiac research.

Beth Pino-Mauch, RN, BSN, works as a nurse care manager in the CPRPs Total Health Study, a blended care intervention trial for patients with comorbid heart disease and mood or anxiety disorders. Beth graduated from Boston College in 1983. She has worked as a cardiac and critical care nurse for over 15 years. Beth has also worked for a Boston-based Academic Research Organization as both a Project Manager, and subsequently, a Clinical Nurse Reviewer of reported Serious Adverse Events in several FDA-monitored medical device trials for coronary intervention.

Melanie Freedman, BS, graduated cum laude from Northeastern University in 2015 with a degree in psychology. She is a senior member of the CPRP, serving as the primary research coordinator for the REACH for Health Study. In this role, she is responsible for recruitment, enrollment, and managing study materials. She is also serving as the sole interventionist for a pilot trial of a positive psychology intervention in patients with Multiple Sclerosis through the Partners MS Center (PI: Glanz). Previously, Melanie worked as a research assistant at the Lifespan Emotional Development Lab at Northeastern University, which investigated emotion regulation and attention throughout the lifespan. She then worked as a Resource Specialist on the inpatient psychiatric unit at MGH before joining the CPRP.

Diana Smith, BA, graduated magna cum laude from Harvard University in 2017, with a degree in cognitive neuroscience and evolutionary psychology. She is in her second year with the CPRP and primarily manages the Total Health study, a blended care intervention trial for patients with comorbid heart disease and mood or anxiety disorders. She is also the primary coordinator for an ongoing project (PI: Nock), which is a real-time assessment of suicidal thoughts among psychiatric inpatients. In addition to her role at the CPRP, she volunteers for Samaritans, a suicide prevention and crisis line in Boston. Diana is currently applying to MD/PhD programs to begin in Fall 2019.

Sonia Kim, BA, graduated from UCLA in 2015 summa cum laude with a degree in psychology. She is in her first year with the program and is serving as the primary research coordinator for the MAPP (a PP-MI behavioral intervention study for patients with metabolic syndrome) and NCCP (a pilot care management intervention project for patients with non-cardiac chest pain). Before joining the CPRP, she worked as a rehabilitation specialist at the Sound End Community Health Center, working with underserved population that suffers from severe psychiatric illnesses. Previously in college, she was involved in an fMRI research in Dr. Matthew Liebermans lab, investigating the neural and behavioral effects of neuropeptides on human social cognition.

Julia Golden, BA, graduated from Mount Holyoke College in 2015 summa cum laude with a degree in psychology. Currently in her first year with the program, she is serving as the primary research coordinator for the BEHOLD studies. In this role, she is responsible for recruiting and enrolling diabetes patients as well as for organizing and managing study-related data. Previously, Julia worked as a research assistant at the Institute of Living, Hartford Hospitals psychiatric division, and was involved in studies related to mood disorders and metabolic syndrome in young adult patients. This past year she completed a post-baccalaureate pre-medical program at the University of Virginia.

Carlyn Scheu, BS, graduated cum laude from the University of Denver in 2018 with a degree in biology and psychology. In her first year with the program, Carlyn works primarily on the Dexmedetomidine study, a trial for the use of a sedative drug in patients with probable Alzheimers disease. She is also the primary coordinator for the PATH study, which focuses on a positive psychology intervention for cancer patients who have had a hematopoietic stem cell transplant. Prior to her involvement with the CPRP, Carlyn worked as a research assistant for the Traumatic Stress Studies Group at the University of Denver, which seeks to understand complex consequences of trauma and how to improve outcomes for trauma survivors.

Brian Healy, PhD,is an Assistant Professor in the Department of Neurology at Harvard Medical School, a member of the Biostatistics Center at Mass General, and an Instructor in Biostatistics at the Harvard School of Public Health. Dr. Healy is also the lead biostatistician for the Partners Multiple Sclerosis Center, which is affiliated with Brigham and Women's Hospital. His primary research interest is statistical methods development and application for modeling of multiple sclerosis. He has been working with the CPRP for the past 5 years, and he has participated in the design and analysis of several studies.

Elizabeth Madva, MD, is a fourth year resident in the MGH/McLean psychiatry residency program and a member of the residency's Research Concentration Program and Clinician Educator Program. She is currently serving as the administrative chief resident and the Mass General Consultation-Liaison Psychiatry chief resident. She graduated from Weill Cornell Medical College in 2015 and from Yale University in 2008, magna cum laude, with a BA in Cognitive Science. She is a member of the Alpha Omega Alpha and Phi Beta Kappa honor societies. She began working with the CPRP in 2016 at the end of her first year of residency. Her clinical and research interests fall in the areas of consultation-liaison psychiatry and neuropsychiatry, with a special interest in somatic symptom and functional neurological disorders.

Hermioni Lokko, MD, MPP, is an Instructor in Psychiatry at Harvard Medical School (HMS) as well as, staff physician on the Medical Psychiatry Service at Brigham and Women's Hospital (BWH) and the Department of Psychosocial Oncology and Palliative Care at the Dana-Farber Cancer Institute (DFCI). She is also the Associate Training Director of the BWH/HMS psychiatry residency training Program. Her areas of interest include the impact of psychiatric illness, management strategies and palliative care in diverse cancer patients to develop innovative and practical psychological interventions for cancer patients and their care givers. She is currently the principal investigator for a Harvard Medical School funded project seeking to develop a positive psychology intervention to improve function and quality of life in hematopoietic stem cell transplant patients. She is an active co-investigator for the PEACE trial and assists with other projects at the CPRP. She is a graduate of the psychosomatic medicine/psycho-oncology fellowship at the BWH and DFCI, the adult psychiatry residency training program at the Mass General and McLean Hospital, Harvard Medical School and Harvard Kennedy School of Government.

Medical Students:

Residents:

Faculty/Fellows:

Research Coordinators:

Social Work and Nursing Interventionists:

Our work has also been generously supported by the esteemed Avery D. Weisman, MD, of the eponymous Mass General Psychiatry Consultation Service and a long-standing national leader in psychosomatic medicine. His support has allowed the CPRP to continue to investigate the associations between positive and negative emotional states and physical health and well-being, and we are forever indebted.

Read the original:
Cardiac Psychiatry Research Program - Massachusetts ...

Theranostics 2017; 7(7):2067-2077. doi:10.7150/thno.19427

Review

Kiwon Ban1, Seongho Bae2, Young-sup Yoon2, 3

1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong;2. Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA;3. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) are considered a most promising option for cell-based cardiac repair. Hence, various protocols have been developed for differentiating hPSCs into CMs. Despite remarkable improvement in the generation of hPSC-CMs, without purification, these protocols can only generate mixed cell populations including undifferentiated hPSCs or non-CMs, which may elicit adverse outcomes. Therefore, one of the major challenges for clinical use of hPSC-CMs is the development of efficient isolation techniques that allow enrichment of hPSC-CMs. In this review, we will discuss diverse strategies that have been developed to enrich hPSC-CMs. We will describe major characteristics of individual hPSC-CM purification methods including their scientific principles, advantages, limitations, and needed improvements. Development of a comprehensive system which can enrich hPSC-CMs will be ultimately useful for cell therapy for diseased hearts, human cardiac disease modeling, cardiac toxicity screening, and cardiac tissue engineering.

Keywords: Cardiomyocytes, hPSCs

Heart failure is the leading cause of death worldwide [1]. Approximately 6 million people suffer from heart failure in the United States every year [1]. Despite this high incidence, existing surgical and pharmacological interventions for treating heart failure are limited because these approaches only delay the progression of the disease; they cannot directly repair the damaged hearts [2]. In the case of large myocardial infarction (MI), patients progress to heart failure and die within short time from the onset of symptoms [3].

The adult human heart has minimal regenerative capacity, because during mammalian development, the proliferative capacity of cardiomyocytes (CMs) progressively diminishes and becomes terminally differentiated shortly after birth [4].Therefore, once CMs are damaged, they are rarely restored [5]. When MI occurs, the infarcted area is easily converted to non-contractile scar tissue due to loss of CMs and replacement by fibrosis [6]. Development of a fibroblastic scar initiates a series of events that lead to adverse remodeling, hypertrophy, and eventual heart failure [2, 3, 7].

While heart transplantation is considered the most viable option for treating advanced heart failure, the number of available donor hearts is always less than needed [6]. Therefore, more realistic therapeutic options have been required [2]. Accordingly, over the past two decades, cell-based cardiac repair has been intensively pursued [2, 7]. Several different cell types have been tested and varied outcomes were obtained. Indeed, the key factor for successful cell-based cardiac repair is to find the optimal cell type that can restore normal heart function. Naturally, CMs have been considered the best cell type to repair a damaged heart [8]. In fact, many scientists hypothesized that implanted CMs would survive in damaged hearts and form junctions with host CMs and synchronously contract with the host myocardium [9]. In fact, animal studies with primary fetal or neonatal CMs demonstrated that transplanted CMs could survive in infarcted hearts [9-11]. These primary CMs reduced scar size, increased wall thickness, and improved cardiac contractile function with signs of electro-mechanical integration [9-11]. These studies strongly suggest that CMs can be a promising source to repair the heart. However, the short supply and ethical concerns disallow using primary human CMs. In a patient with ischemic cardiomyopathy, about 40-50% of the CMs are lost in 40 to 60 grams of heart tissue [7]. Even if we seek to regenerate a fairly small portion of the damaged myocardium, a large number of human primary CMs would be required, which is impossible.

Accordingly, CMs differentiated from human pluripotent stem cells (hPSCs) including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have emerged as a promising option for candidate CMs for cell therapy [12, 13]. hPSCs have many advantages as a source for CMs. First, hPSCs have obvious cardiomyogenic potential. hPSC derived-CMs (hPSC-CMs) possess a clear cardiac phenotype, displaying spontaneous contraction, cardiac excitation-contraction (EC) coupling, and expression of cardiac transcription factors, cardiac ion channels, and cardiac structural proteins [14, 15]. Second, undifferentiated hPSCs and their differentiated cardiac progeny display significant proliferation capacity, allowing generation of a large number of hPSC-CMs. Lastly, many pre-clinical studies demonstrated that implantation of hPSC-CMs can repair injured hearts and improve cardiac function [16-19]. Histologically, implanted hPSC-CMs are engrafted, aligned and coupled with the host CMs in a synchronized manner [16-19].

In the last two decades, various protocols for differentiating hPSCs into CMs have been developed to improve the efficiency, purity and clinical compatibility [20] [18]. The reported differentiation methods include, but are not limited to: differentiation via embryoid body (EB) formation [20], co-culture with END-2 cells [18], and monolayer culture [15, 21, 22]. The EB-mediated CM differentiation protocol is one of the most widely employed methods due to its simple procedure and low cost. However, it often becomes labor-intensive to produce scalable EBs for further differentiation, which makes it difficult for therapeutic applications. EB-mediated differentiation also produces inconsistent results, showing beating CMs from 5% to 70% of EBs. Recently, researchers developed monolayer methods to complement the problems of EB-based methods [15, 21, 22]. In one representative protocol, hPSCs are cultured at a high density (up to 80%) and treated with a high concentration of Activin A (100 ng/ml) for 1 day and BMP4 (10 ng/ml) for 4 days followed by continuous culture on regular RPMI media with B27 [15]. This protocol induces spontaneous beating at approximately 12 days and produces approximately 40% CMs after 3 weeks. These hPSC-CMs can be further cultured in RPMI-B27 medium for another 2-3 weeks without significant cell damage [15]. However, these protocols use media with proprietary formulations, which complicates clinical application. As shown, most monolayer-based methods employ B27, which is a complex mix of 21 components. Some of the components of B27, including bovine serum albumin (BSA), are animal-derived products, and the effects of B27 components on differentiation, maturation or subtype specification processes are poorly defined. In 2014, Burridge and his colleagues developed an advanced protocol that is defined, cost-effective and efficient [22]. By subtracting one component from B27 at a time and proceeding with cardiac differentiation, the researchers reported that BSA and L-ascorbic acid 2-phosphate are essential components in cardiac differentiation. Subsequently, by replacing BSA with rice-derived recombinant human albumin, the chemically defined medium with 3 components (CDM3) was produced. The application of a GSK-inhibitor, CHIR99021, for the first 2 days followed by 2 days of the Wnt-inhibitor Wnt-59 to cells is an optimal culture condition in CDM3 resulting in similar levels of live-cell yields and CM differentiation [22].

Despite remarkable improvement in the generation of hPSC-CMs, obtaining pure populations of hPSC-CMs still remains challenging. Currently available methods can only generate a mixture of cells which include not only CMs but other cell types. This is one of the most critical barriers for applications of hPSC-CMs in regenerative therapy, drug discovery, and disease investigation. For Instance, cardiac transplantation of non-pure hPSC-CMs mixed with undifferentiated hPSCs or other cell types may produce tumors or unwanted cell types in hearts [23-28]. Accordingly, a pure or enriched population of hPSC-CMs would be required, particularly for cardiac cell therapy. Enriched hPSC-CMs would also be more beneficial for myocardial repair due to improved electric and mechanical properties [29]. A pure, homogeneous population of hPSC-CMs would pose less arrhythmic risk and have enhanced contractile performance, and would be more useful in disease modeling as they better reflect native CM physiology. Finally, purified hPSC-CMs would better serve for testing drug efficacy and toxicity. Therefore, many researchers have tried to develop methods to purify CMs from cardiomyogenically differentiated hPSCs.

There are three important topics that are not addressed in this review. First is the beneficial role of other cell types such as endothelial cells and fibroblasts in the integration, survival, and function of CMs [30-32]. We did not discuss this issue because it would need a separate review due to the volume of material. While the roles of such cells are important, the value of having purified hPSC-CMs is not diminished. Although cell mixtures or tissue engineered products can be used, unless purified CMs are employed, they would form tumors or other cells/tissues when implanted in vivo. Our point here is that even if cardiomyocytes are mixed with non-CMs, all cells should be clearly defined and purified as well. If the mixture is made in a non-purified or non-defined manner (for example, an unsophisticated top-down approach), there would be undefined cells that are neither CMs, ECs, nor fibroblasts and these unidentified cells will make aberrant tissues or tumors. Second, we did not deal with maturation of hPSC-CMs because of its broad scope and depth [33, 34]. Third is direct reprogramming or conversion of somatic cells into CMs. There has been another advancement in the generation of CMs by directly reprogramming or converting somatic cells into CM-like cells by introducing a combination of cardiac transcription factors (TFs) or muscle-specific microRNAs (miRNAs) both in vitro and in vivo [35-41]. These cells are referred to as induced CMs (iCMs) or cardiac-like myocytes (iCLMs). While this is an important advancement, we did not cover this topic either due to its size. Accordingly, this review will focus on the various strategies for purifying or enriching hPSC-CMs reported to date (Figure 1).

Early on, researchers isolated hPSC-CMs manually under microscopy by mechanically separating out the beating areas from myogenically differentiating hPSC cultures [18, 20, 42]. This method usually generates 5-70% hPSC-CMs. Although generally crude, it can enrich even higher percentages of CMs with further culture. This manual isolation method has the advantage of being easy, but while it can be useful for small-scale research, it is very labor intensive and not scalable, precluding large scale research or clinical application.

Currently available strategies for enriching cardiomyocytes derived from human pluripotent stem cells.

Xu et el. reported that hPSC-CMs, due to their physical and structural properties, can be enriched by Percoll density gradient centrifugation [43]. Percoll was first formulated by Pertoft et al [44] and it was originally developed for the isolation of cells, organelles, or viruses by density centrifugation. The Percoll-based method has several advantages. The procedure for Percoll-based separation is very simple and easy, it is inexpensive, and its low viscosity allows more rapid sedimentation and lower centrifugal forces compared to a sucrose density gradient. Lastly, it can be prepared and kept for a long time in an isotonic solution to maintain osmolarity. Although Percoll separation has resulted in major improvements in hPSC-CM isolation procedures, it has clear limitations with regard to purity and scalability. Previous studies found that Percoll separation is only able to enrich 40 -70% of hPSC-CMs. It is also not compatible with large-scale enrichment of hPSC-CMs.

Another traditional method for purifying hPSC-CMs is based on the expression of a drug resistant gene or a fluorescent reporter gene such as eGFP or DsRed, which is driven by a cardiac specific promoter in genetically modified hPSC lines [45, 46]. Here, enrichment of hPSC-CMs can be achieved by either drug treatment to eliminate cells that do not express the drug resistant gene or with FACS to isolate fluorescent cells [47, 48].

Briefly, enrichment of PSC-CMs by genetically based selection was first reported by Klug et al [49]. The authors generated murine ES cell lines via permanent gene transfection of the aminoglycoside phosphotransferase gene driven by the MHC (MYH7) promoter. With this approach, highly purified murine ESC-CMs up to 99% were achieved. Next, several studies reported the use of various CM-specific promoters to enrich ESC-CMs such as Mhc (Myh6), Myh7, Ncx (Sodium Calcium exchanger) and Mlc2v (Myl2) [46, 50, 51]. In the case of hESCs, MHC/EGFP hESCs were generated by permanent transfection of the EGFP-tagged MHC promoter [52]. Similarly, an NKX2.5/eGFP hESC line was generated to enrich GFP positive CMs [53]. However, since MHC and NKX2.5 are expressed in general CMs, the resulting CMs contain a mixture of the three subtypes of CMs, nodal-, atrial-, and ventricular-like CMs. To enrich only ventricular-like CMs, Huber et al. generated MLC2v/GFP ESCs to be able to isolate MLC2v/GFP positive ventricular-like cells by FACS [52] [54-57]. In addition, the cGATA6 gene was used to purify nodal-like hESC-CMs [58]. Future studies should focus on testing new types of cardiac specific promoters and devising advanced selection procedures to improve this strategy.

While fluorescence-based cell sorting is more widely used, the drug selection method may be a better approach to enrich high purity of hPSC-CMs during differentiation/culture as it does not require FACS. The advantage is its capability for high-purity cell enrichment due to specific gene-based cell sorting. These highly pure cells can allow more precise mechanistic studies and disease modeling. Despite its many advantages, the primary weakness of genetic selection is genetic manipulation, which disallows its use for therapeutic application. Insertion of reporter genes into the host genome requires viral or nonviral transfection/transduction methods, which can induce mutagenesis and tumor formation [50, 59-61].

Practically, antibody-based cell enrichment is the best method for cell purification to date. When cell type-specific surface proteins or marker proteins are known, one can tag cells with antibodies against the proteins and sort the target cells by FACS or magnetic-activated cell sorting (MACS). The main advantage is its specificity and sensitivity, and its utility is well demonstrated in research and even in clinical therapy with hematopoietic cells [62]. Another advantage is that multiple surface markers can be used at the same time to isolate target cells when one marker is not sufficient. However, no studies have reported surface markers that are specific for CMs, even after many years. Recently, though, several researchers demonstrated that certain proteins can be useful for isolating hPSC-CMs.

In earlier studies, KDR (FLK1 or VEGFR2) and PDGFR- were used to isolate cardiac progenitor cells [63]. However, since these markers are also expressed on hematopoietic cells, endothelial cells, and smooth muscle cells, they could not enrich only hPSC-CMs. Next, two independent studies reported two surface proteins, SIRPA [64] and VCAM-1 [65], which it was claimed could specifically identify hPSC-CMs. Dubois et al. screened a panel of 370 known antibodies against CMs differentiated from hESCs and identified SIRPA as a specific surface protein expressed on hPSC-CMs [64]. FACS with anti-SIRPA antibody enabled the purification of CMs and cardiac precursors from cardiomyogenically differentiating hPSC cultures, producing cardiac troponin T (TNNT2, also known as cTNT)-positive cells, which are generally considered hPSC-CMs, with up to 98% purity. In addition, a study performed by Elliot and colleagues identified another cell surface marker, VCAM1 [53]. In this study, the authors used NKX2.5/eGFP hESCs to generate hPSC-CMs, allowing the cells to be sorted by their NKX2.5 expression. NKX2.5 is a well-known cardiac transcription factor and a specific marker for cardiac progenitor cells [66, 67]. To identify CM-specific surface proteins, the authors performed expression profiling analyses and found that expression levels of both VCAM1 and SIRPA were significantly upregulated in NKX2.5/eGFP+ cells. Flow cytometry results showed that both proteins were expressed on the cell surface of NKX2.5/eGFP+ cells. Differentiation day 14 NKX2.5/eGFP+ cells expressed VCAM1 (71 %) or SIRPA (85%) or both VCAM1 and SIRPA (37%). When the FACS-sorted SIRPA-VCAM1-, SIRPA+ or SIRPA+VCAM1+ cells were further cultured, only SIRPA+ or SIRPA+VCAM1+ cells showed NKX2.5/eGFP+ contracting portion. Of note, NKX2.5/eGFP and SIRPA positive cells showed higher expression of smooth muscle cell and endothelial cell markers indicating that cells sorted solely based on SIRPA expression may not be of pure cardiac lineage. Hence, the authors concluded that a more purified population of hPSC-CMs could be isolated by sorting with both cell surface markers. Despite significant improvements, it appears that these surface markers are not exclusively specific for CMs as these antibodies also mark other cell types including smooth muscle cells and endothelial cells. Furthermore, they are also known to be expressed in the brain and the lung, which raises concerns whether these surface proteins can be used as sole markers for the purification of hPSC-CMs compatible for clinical applications.

More recently, Protze et al. reported successful differentiation and enrichment of sinoatrial node-like pacemaker cells (SANLPCs) from differentiating hPSCs by using cell surface markers and an NKX2-5-reporter hPSC line [68]. They found that BMP signaling specified cardiac mesoderm toward the SANLPC fate and retinoic acid signaling enhanced the pacemaker phenotype. Furthermore, they showed that later inhibition of the FGF pathway, the TFG pathway, and the WNT pathway shifted cell fate into SANLPCs, and final cell sorting for SIRPA-positive and CD90-negative cells resulted in enrichment of SANLPCs up to ~83%. These SIRPA+CD90- cells showed the molecular, cellular and electrophysiological characteristics of SANLPCs [68]. While this study makes important progress in enriching SANLPCs by modulating signaling pathways, no specific surface markers for SANLPCs were identified and the yield was still short of what is usually expected for cells purified via FACS.

Hattori et al. developed a highly efficient non-genetic method for purifying hPSC-derived CMs, in which they employed a red fluorescent dye, tetramethylrhodamine methyl ester perchlorate (TMRM), that can label active mitochondria. Since CMs contain a large number of mitochondria, CMs from mice and marmosets (monkey) could be strongly stained with TMRM [69]. They further found that primary CMs from several different types of animals and CMs derived from both mESCs and hESCs were successfully purified by FACS up to 99% based on the TMRM signals. In addition to its efficiency for CM enrichment, TMRM did not affect cell viability and disappeared completely from the cells within 24 hrs. Importantly, injected hPSC-CMs purified in this way did not form teratoma in the heart tissues. However, since TMRM only functions in CMs with high mitochondrial density, this method cannot purify entire populations of hPSC-CMs [64]. While originally TMRM was claimed to be able to isolate mature hPSC-CMs, mounting evidence indicates that hPSC-CMs are similar to immature human CMs at embryonic or fetal stages. Therefore, both the exact phenotype of the cells isolated by TMRM and its utility are rather questionable [33, 34]. Two subsequent studies demonstrated that TMRM failed to accurately distinguish hPSC-CMs due to the insufficient amounts of mitochondria [64].

Employing the unique metabolic properties of CMs, Tohyama et al. developed an elegant purification method to enrich PSC-CMs [70]. This approach is based on the remarkable biochemical differences in lactate and glucose metabolism between CMs and non-CMs, including undifferentiated cells. Mammalian cells use glucose as their main energy source [71]. However, CMs are capable of energy production from different sources such as lactate or fatty acids [71]. A comparative transcriptome analysis was performed to detect metabolism-related genes which have different expression patterns between newborn mouse CMs and undifferentiated mouse ESCs. These results showed that CMs expressed genes encoding tricarboxylic acid (TCA) cycle enzymes more than genes related to lipid and amino acid synthesis and the pentose phosphate cycle compared to undifferentiated ESCs. To further prove this observation, they compared the metabolites of these pathways using fluxome analysis between CMs and other cell types such as ESCs, hepatocytes and skeletal muscle cells, and found that CMs have lower levels of metabolites related to lipid and amino acid synthesis and pentose phosphate. Subsequently, authors cultured newborn rat CMs and mouse ESCs in media with lactate, forcing the cells to use the TCA cycle instead of glucose, and they observed that CMs were the only cells to survive this condition for even 96 hrs. They further found that when PSC derivatives were cultured in lactate-supplemented and glucose-depleted culture medium, only CMs survived. Their yield of CM population was up to 99% and no tumors were formed when these CMs were transplanted into hearts. This lactate-based method has many advantages: its simple procedures, ease of application, no use of FACS for cell sorting, and relatively low cost. More recently, this method was applied to large-scale CM aggregates to ensure scalability. As a follow-up study, the same group recently reported a more refined lactate-based enrichment method which further depletes glutamine in addition to glucose [72]. The authors found that glutamine is essential for the survival of hPSCs since hPSCs are highly dependent on glycolysis for energy production rather than oxidative phosphorylation. The use of glutamine- and glucose-depleted lactate-containing media resulted in more highly purified hPSC-CMs with less than 0.001% of residual PSCs [72]. One concern of this lactate-based enrichment method is the health of the purified hPSC-CMs, because physiological and functional characteristics of hPSC-CMs cultured in glucose- and glutamine-depleted media for a long time may have functional impairment since CMs with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate [72]. In addition, this lactate-based strategy can only be applied to hPSC- CMs, but not other hPSC derived cells such as neuron or -cells.

Our group also recently reported a new method to isolate hPSC-CMs by directly labelling cardiac specific mRNAs using nano-sized probes called molecular beacons (MBs) [29, 73, 74]. Designed to detect intracellular mRNA targets, MBs are dual-labeled antisense oligonucleotide (ODN) nano-scale probes with a DNA or RNA backbone, a Cy3 fluorophore at the 5' end, and a Black Hole quencher 2 (BHQ2) at the 3' end [75, 76]. They form a stem-loop (hairpin) structure in the absence of a complementary target, quenching the fluorescence of the reporter. Hybridization with the target mRNA opens the hairpin and physically separates the reporter from the quencher, allowing a fluorescence signal to be emitted upon excitation. The MB-based method can be applied to the purification of any cell type that has known specific gene(s) [77].

In one study [29], we designed five MBs targeting unique sites in TNNT2 or MYH6/7 mRNA in both mouse and human. To determine the most efficient transfection method to deliver MBs into living cells, various methods were tested and nucleofection was found to have the highest efficiency. Next, we tested the sensitivity and specificity of MBs using an immortalized mouse CM cell line, HL-1, and other cell types. Finally, we narrowed it down to one MB, MHC-MB, which showed >98% sensitivity and > 95% specificity. This MHC-MB was applied to cardiomyogenically differentiated mouse and human PSCs and FACS sorting was performed. The resultant MHC-MB-positive cells expressed cardiac proteins at ~97% when measured by flow cytometry. These sorted cells also demonstrated spontaneous contraction and all the molecular and electrophysiological signatures of human CMs. Importantly, when these purified CMs were injected into the mouse infarcted myocardium, they were well integrated into the myocardium without forming any tumors, and they improved cardiac function.

In a subsequent study [74], we refined a method to enrich ventricular CMs from differentiating PSCs (vCMs) by targeting a transcription factor which is not robustly expressed in cells. Since vCMs are the main source for generating cardiac contractile forces and the most frequently damaged in the heart, there has been great demand to develop a method that can obtain a pure population of vCMs for cardiac repair. Despite this critical unmet need, no studies have demonstrated the feasibility of isolating ventricular CMs without permanently altering their genome. Accordingly, we first designed MBs targeting the Iroquois homeobox protein 4 (Irx4) mRNA, a vCM specific transcription factor [78, 79]. After testing sensitivity and specificity, one IRX4-MB was selected and applied to myogenically differentiated mPSCs. The FACS-sorted IRX4-MB-positive cells exhibited vCM-like action potentials in more than 98% of cells when measured by several electrophysiological analyses including patch clamp and Ca2+ transient analyses. Furthermore, these cells maintained spontaneous contraction and expression of vCM-specific proteins.

The MB-based cell purification method is theoretically the most broadly applicable technology among the purification methods because it can isolate any target cells expressing any specific gene. Thus, the MB-based sorting technique can be applied to the isolation of other cell types such as neural-lineage cells or islet cells, which are critical elements in regenerative medicine but do not have specific surface proteins identified to date. In addition, theoretically, this technology may have the highest efficiency when MBs are designed to have the maximum sensitivity and specificity for the cells of interest, but not others. These characteristics are particularly important for cell therapy. Despite these advantages, the delivery method of MB into the cells needs to be improved. So far, nucleofection is the best delivery method, but caused some cell damage with < 70% cell viability. Thus, development of a safer delivery method will enable wider application of MB-based cell enrichment.

Recently, Miki and colleagues reported a novel method for purifying cells of interest based on endogenous miRNA activity [80]. Miki et al. employed several synthetic mRNA switches (= miRNA switch), which consist of synthetic mRNA sequences that include a recognition sequence for miRNA and an open reading frame that codes a desired gene, such as a regulatory protein that emits fluorescence or promotes cell death. If the miRNA recognition sequence binds to miRNA expressed in the desired cells, the expression of the regulatory protein is suppressed, thus distinguishing the cell type from others that do not contain the miRNA and express the protein.

Briefly, the authors first identified 109 miRNA candidates differentially expressed in distinct stages of hPSC-CMs (differentiation day 8 and 20). Next, they found that 14 miRNAs were co-expressed in hPSC-CMs at day 8 and day 20 and generated synthetic mRNAs that recognize these 14 miRNA, called miRNA switches. Among those miRNA switches, miR-1-, miR-208a-, and miR-499a-5p-switches successfully enriched hPSC-CMs with purity of sorted cells up to 96% determined by TNNT2 intracellular flow cytometry. Particularly, hPSC-CMs enriched by the miR-1-switch showed substantially higher expression of several cardiac specific genes/proteins and lower expression of non-CM genes/proteins compared with control cells. Patch clamp confirmed that these purified hPSC-CMs possessed both ventricular-like and atrial-like action potentials.

One of the major advantages of this technology is its wider applicability to other cell types. miRNA switches have the flexibility to design the open reading frame in the mRNA sequence such that any desired transgene can be incorporated into the miRNA switches to regulate the cell phenotype based on miRNA activity. The authors tested this possibility by incorporating BIM sequence, an apoptosis inducer, into the cardiac specific miR-1- and miR-208a switches and tested whether they could selectively induce apoptosis in non-CMs. They found that miR-1- and miR-208a-Bim-switches successfully enriched cTNT-positive hPSC-CMs without cell sorting. Enriched hPSC-CMs by 208a-Bim-switch were injected into the hearts of mice with acute MI and they engrafted, survived, expressed both cTNT and CX43, and formed gap junctions with the host myocardium. No teratoma was detected. In addition, other miRNA switches such as miR-126-, miR-122-5p-, and miR-375-switches targeting endothelial cells, hepatocytes, and -cells, respectively, successfully enriched these cell types differentiated from hPSCs. However, identification of specific miRNAs expressed only in the specific cell type of interest and verification of their specificity in target cells will be key issues for continuing to use this miRNA-based cell enrichment method.

Recent advances in biomedical engineering have contributed to developing systems that can isolate target cells using physicochemical properties of the cells. Microfluidic systems have been intensively applied for cell separation due to recent improvements in miniaturizing a cell culture system [81-83]. These advances made possible the design of automated microfluidic devices with cellular microenvironments and controlled fluid flows that save time and cost in experiments. Thus, there have been an increasing number of studies seeking to apply the microfluidic system for cell separation. Among the first, Singh et al. tested the possibility of using a microfluidic system for the separation of hPSC [84] by preparative detachment of hPSCs from differentiating cultures based on differences in the adhesion properties of different cell types. Distinct streams of buffer that generated varying levels of shear stress further allowed selective enrichment of hPSC colonies from mixed populations of adherent non-hPSCs, achieving up to 95% purity. Of note, this strategy produced hPSC survival rates almost two times higher than FACS, reaching 80%.

Subsequently, for hPSC-CMs purification, Xin et al. developed a microfluidic system with integrated ridge-like flow derivations and fishnet-like microcolumns for the enrichment of hiPSC-CMs [85]. This device is composed of a 250 mm-long microfluidic channel, which has two integrated parallel microcolumns with surfaces functionalized with anti-human TRA-1 antibody for undifferentiated hiPSC trapping. Aided by the ridge-like surface patterns on the upper wall of the channel, micro-streams are generated so that the cell suspension of mixed undifferentiated hiPSCs and hiPSC-CMs are forced to cross the functionalized fishnet-like microcolumns, resulting in trapping of undifferentiated hiPSCs due to the interaction between the hiPSCs and the columns, and the untrapped hiPSC-CMs are eventually separated. By modulating flow and coating with anti-human TRA-1 antibody, they were able to enrich CMs to more than 80% purity with 70% viability. While this study demonstrated that a microfluidic device could be used for purifying hPSC-CMs, it was not realistic because the authors used a mixture of only undifferentiated hiPSCs and hiPSC-CMs. In real cardiomyogenically differentiated hiPSCs, undifferentiated hiPSCs are rare and many intermediate stage cells or other cell types are present, so the idea that this simple device can select only hiPSC-CMs from a complex mixture is uncertain.

Overall, the advantages of microfluidic system based cell isolation include fast speed, improved cell viability and low cost owing to the automated microfluidic devices that can control cellular microenvironments and fluid flows [86-88]. However, microfluidic-based cell purification methods have limitations in terms of low purity and scalability [89-92]. In fact, there have been only a few studies demonstrating the feasibility that microfluidic device-based cell separation could achieve higher than 80% purity of target cells. Furthermore, currently available microfluidic devices allow only separation of a small number of cells (< 1011). To employ microfluidic devices for large-scale cell production, we need to develop a next generation of microfluidic devices that can achieve a throughput greater than 1011 sorted cells per hour with > 95% purity.

Having available a large quantity of a homogeneous population of cells of interest is an important factor in advancing biomedical research and clinical medicine, and is especially true for hPSC-CMs. While remarkable progress has been made in the methods for differentiating hPSCs into CMs, technologies to enrich hPSC-CMs, particularly those which are clinically applicable, have been emerging only over the last few years. Contamination with other cell types and even the heterogeneous nature of hPSC-CMs significantly hinder their use for several future applications such as cardiac drug toxicology screening, human cardiac disease modeling, and cell-based cardiac repair. For instance, cardiac drug-screening assays require pure populations of hPSC-CMs, so that the observed signals can be attributed to effects on human CMs. Studies of human cardiac diseases can also be more adequately interpreted with purified populations of patient derived hiPSC-CMs. Clinical applications with hPSC-CMs will need to be free of other PSC derivatives to minimize the risk of teratoma formation and other adverse outcomes.

Summary of representative methods for hPSC-CM purification

Schematic pictures of microfluidic device for enriching hiPSC-CMs. (A) The part of the device designed for trapping undifferentiated hiPSCs. (B) (Left) Illustration of the overall microfluidic device assembled with peristaltic pump, cell suspension reservoirs, and a serpentine channel. (Right) Magnified image showing a channel combining microcolumns and ridge-like flow derivation structures. Modified from Li et al. On chip purification of hiPSC-derived cardiomyocytes using a fishnet-like microstructure. Biofabrication. 2016 Sep 8;8(3): 035017

Therefore, development of reproducible, effective, non-mutagenic, scalable, and economical technologies for purifying hPSC-CMs, independent of hPSC lines or differentiation protocols, is a fundamental requirement for the success of hPSC-CM applications. Fortunately, new technologies based on the biological specificity of CMs such as MITO-tracker, molecular beacons, lactate-enriched-glucose depleted-media, and microRNA switches have been developed. In addition, technologies based on engineering principles have recently yielded a promising platform using microfluidic technology. While due to the short history of this field, more studies are needed to verify the utility of these technologies, the growing attention toward this research is a welcome move.

Another important question raised recently is how to non-genetically purify chamber-specific subtypes of CMs such as ventricular-like, atrial-like and nodal-like hPSC-CMs. So far, only a few studies have addressed this potential with human PSCs. We also showed that a molecular beacon-based strategy could enrich ventricular CMs differentiated from PSCs [74]. Another study demonstrated generation of SA-node like pacemaker cells by using a stepwise treatment of various morphogens and small molecules followed by cell sorting with several sub-specific surface markers. However, the yield of both studies was relatively low (<85%). Given the growing clinical importance of chamber-specific CMs, the strategies for purifying specific subtypes of CM that are independent of hPSC lines or differentiation protocols should be continuously developed. A recently reported cell surface capture-technology [93, 94] may facilitate identification of chamber specific CM proteins that will be useful for target CM isolation.

In summary, technological advances in the purification of hPSC-CMs have opened an avenue for realistic application of hPSC-CMs. Although initial success was achieved for purification of CMs from differentiating hPSC cultures, questions such as scalability, clinical compatibility, and cellular damage remain to be answered and isolation of human subtype CMs has yet to be demonstrated. While there are other challenges such as maturity, in vivo integration, and arrhythmogenecity, this development of purification technology represents major progress in the field and will provide unprecedented opportunities for cell-based therapy, disease modeling, drug discovery, and precision medicine. Furthermore, the availability of chamber-specific CMs with single cell analyses will facilitate more sophisticated investigation of human cardiac development and cardiac pathophysiology.

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No 2015M3A9C6031514), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2782, HI16C2211) and grants from NHLBI (R01HL127759, R01HL129511), NIDDK (DP3-DK108245). This work was also supported by a CityU Start-up Grant (No 7200492), a CityU Research Project (No 9610355), and a Georgia Immuno Engineering Consortium through funding from Georgia Institute of Technology, Emory University, and the Georgia Research Alliance.

The authors have declared that no competing interest exists.

1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M. et al. Heart disease and stroke statistics2016 update. Circulation. 2016;133:e38-e360

2. Ptaszek LM, Mansour M, Ruskin JN, Chien KR. Towards regenerative therapy for cardiac disease. Lancet. 2012;379:933-42

3. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007-18

4. Pasumarthi KBS, Field LJ. Cardiomyocyte cell cycle regulation. Circ Res. 2002;90:1044-54

5. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnab-Heider F, Walsh S. et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98-102

6. Passier R, van Laake LW, Mummery CL. Stem-cell-based therapy and lessons from the heart. Nature. 2008;453:322-9

7. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473:326-35

8. Tulloch NL, Muskheli V, Razumova MV, Korte FS, Regnier M, Hauch KD. et al. Growth of engineered human myocardium with mechanical loading and vascular coculture / Novelty and significance. Circ Res. 2011;109:47-59

9. Reinecke H, Zhang M, Bartosek T, Murry CE. Survival, integration, and differentiation of cardiomyocyte grafts: A study in normal and injured rat hearts. Circulation. 1999;100:193-202

10. Leor J, Patterson M, Quinones MJ, Kedes LH, Kloner RA. Transplantation of fetal myocardial tissue into the infarcted myocardium of rat. A potential method for repair of infarcted myocardium?. Circulation. 1996;94:II332-6

11. Li R-K, Mickle DAG, Weisel RD, Zhang J, Mohabeer MK. In vivo survival and function of transplanted rat cardiomyocytes. Circ Res. 1996;78:283-8

12. Shiba Y, Fernandes S, Zhu WZ, Filice D, Muskheli V, Kim J. et al. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature. 2012;489:322-5

13. Shigeru M, Satsuki F, Yukiko I, Takuji K, Noriko Mochizuki O, Shigeo M. et al. Building a new treatment for heart failure-transplantation of induced pluripotent stem cell-derived cells into the heart. Curr Gene Ther. 2016;16:5-13

14. Mignone JL, Kreutziger KL, Paige SL, Murry CE. Cardiogenesis from human embryonic stem cells - Mechanisms and applications. Circulation J. 2010;74:2517-26

15. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25:1015-24

16. Yuasa S, Itabashi Y, Koshimizu U, Tanaka T, Sugimura K, Kinoshita M. et al. Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. Nat Biotechnol. 2005;23:607-11

17. Nemir M, Croquelois A, Pedrazzini T, Radtke F. Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling. Circ Res. 2006;98:1471-8

18. Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R. et al. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation. 2003;107:2733-40

19. Passier R, Oostwaard DW, Snapper J, Kloots J, Hassink RJ, Kuijk E. et al. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells. 2005;23:772-80

20. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108:407-14

21. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M. et al. Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature. 2008;453:524-8

22. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD. et al. Chemically defined generation of human cardiomyocytes. Nat Methods. 2014;11:855-60

23. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein A. et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest. 2001;108:407-14

24. Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP. et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30-41

25. Nussbaum J, Minami E, Laflamme MA, Virag JAI, Ware CB, Masino A. et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 2007;21:1345-57

26. Lee AS, Tang C, Rao MS, Weissman IL, Wu JC. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med. 2013;19:998-1004

27. Masuda S, Miyagawa S, Fukushima S, Sougawa N, Ito E, Takeda M. et al. Emerging innovation towards safety in the clinical application of ESCs and iPSCs. Nat Rev Cardiol. 2014;11:553-4

28. Masuda S, Miyagawa S, Fukushima S, Sougawa N, Okimoto K, Tada C. et al. Eliminating residual iPS cells for safety in clinical application. Protein Cell. 2015;6:469-71

29. Ban K, Wile B, Kim S, Park H-J, Byun J, Cho K-W. et al. Purification of cardiomyocytes from differentiating pluripotent stem cells using molecular beacons that target cardiomyocyte-specific mRNA. Circulation. 2013;128:1897-909

30. Masumoto H, Ikuno T, Takeda M, Fukushima H, Marui A, Katayama S. et al. Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Sci Rep. 2014;4:6716

31. Kensah G, Roa Lara A, Dahlmann J, Zweigerdt R, Schwanke K, Hegermann J. et al. Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro. Eur Heart J. 2013;34:1134-46

32. Thavandiran N, Dubois N, Mikryukov A, Mass S, Beca B, Simmons CA. et al. Design and formulation of functional pluripotent stem cell-derived cardiac microtissues. Proc Natl Acad Sci U S A. 2013;110:E4698-E707

33. Yang X, Pabon L, Murry CE. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res. 2014;114:511-23

34. Robertson C, Tran DD, George SC. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013;31:829-37

35. Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142:375-86

36. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L. et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593-8

37. Jayawardena TM, Egemnazarov B, Finch EA, Zhang L, Payne JA, Pandya K. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110:1465-73

38. Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN. et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485:599-604

39. Nam YJ, Song K, Luo X, Daniel E, Lambeth K, West K. et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110:5588-93

40. Jayawardena TM, Finch EA, Zhang L, Zhang H, Hodgkinson CP, Pratt RE. et al. MicroRNA induced cardiac reprogramming in vivo: Evidence for mature cardiac myocytes and improved cardiac function. Circ Res. 2015;116:418-24

41. Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T. et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A. 2013;110:12667-72

42. Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A. et al. Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol. 2007;50:1884-93

43. Xu C, Police S, Rao N, Carpenter MK. Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circ Res. 2002;91:501-8

44. Pertoft H, Laurent TC, Ls T, Kgedal L. Density gradients prepared from colloidal silica particles coated by polyvinylpyrrolidone (Percoll). Anal Biochem. 1978;88:271-82

45. Doevendans PA, Becker KD, An RH, Kass RS. The utility of fluorescentin vivoreporter genes in molecular cardiology. Biochem Biophys Res Commun. 1996;222:352-8

46. Ritner C, Wong SSY, King FW, Mihardja SS, Liszewski W, Erle DJ. et al. An engineered cardiac reporter cell line identifies human embryonic stem cell-derived myocardial precursors. PLoS One. 2011;6:e16004

47. Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ. et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol. 2011;301:H2006-H17

48. Xu XQ, Zweigerdt R, Soo SY, Ngoh ZX, Tham SC, Wang ST. et al. Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy. 2008;10:376-89

49. Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest. 1996;98:216-24

50. Anderson D, Self T, Mellor IR, Goh G, Hill SJ, Denning C. Transgenic enrichment of cardiomyocytes from human embryonic stem cells. Mol Ther. 2007;15:2027-36

51. Fu J-D, Jiang P, Rushing S, Liu J, Chiamvimonvat N, Li RA. Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells Dev. 2009;19:773-82

52. Huber I, Itzhaki I, Caspi O, Arbel G, Tzukerman M, Gepstein A. et al. Identification and selection of cardiomyocytes during human embryonic stem cell differentiation. FASEB J. 2007;21:2551-63

53. Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL. et al. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 2011;8:1037-40

54. Bizy A, Guerrero-Serna G, Hu B, Ponce-Balbuena D, Willis BC, Zarzoso M. et al. Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes. Stem Cell Res. 2013;11:1335-47

55. Lee MY, Sun B, Schliffke S, Yue Z, Ye M, Paavola J. et al. Derivation of functional ventricular cardiomyocytes using endogenous promoter sequence from murine embryonic stem cells. Stem Cell Res. 2012;8:49-57

56. MLLER M, FLEISCHMANN BK, SELBERT S, JI GJ, ENDL E, MIDDELER G. et al. Selection of ventricular-like cardiomyocytes from ES cells in vitro. FASEB J. 2000;14:2540-8

57. Zhang Q, Jiang J, Han P, Yuan Q, Zhang J, Zhang X. et al. Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals. Cell Res. 2011;21:579-87

See the article here:
Current Strategies and Challenges for Purification of ...

VetStem Technology: Summary

VetStem Regenerative Cell Therapy is based on a clinical technology licensed from Artecel Inc. Original patents are from the University of Pittsburgh and Duke University.

Adipose-derived regenerative cells are:

VetStem Regenerative Cell (VSRC) therapy delivers a functionally diverse cell population able to communicate with other cells in their local environment. Until recently, differentiation was thought to be the primary function of regenerative cells. However, the functions of regenerative cells are now known to be much more diverse and are implicated in a highly integrated and complex network. VSRC therapy should be viewed as a complex, yet balanced, approach to a therapeutic goal. Unlike traditional medicine, in which one drug targets one receptor, Regenerative Medicine, including VSRC therapy, can be applied in a wide variety of traumatic and developmental diseases. Regenerative cell functions include:

In general, in vitro studies demonstrate that MSCs limit inflammatory responses and promote anti-inflammatory pathways.

Multiple studies demonstrate that MSCs secrete bioactive levels of cytokines and growth factors that support angiogenesis, tissue remodeling, differentiation, and antiapoptotic events.25,28 MSCs secrete a number of angiogenesis-related cytokines such as:28

Adipose-derived MSC studies demonstrate a diverse plasticity, including differentiation into adipo-, osteo-, chondro-, myo-, cardiomyo-, endothelial, hepato-, neuro-, epithelial, and hematopoietic lineages, similar to that described for bone marrow derived MSCs.22 These data are supported by in vivo experiments and functional studies that demonstrated the regenerative capacity of adipose-derived MSCs to repair damaged or diseased tissue via transplant engraftment and differentiation.6,9,30

Homing (chemotaxis) is an event by which a cell migrates from one area of the body to a distant site where it may be needed for a given physiological event. Homing is an important function of MSCs and other progenitor cells and one mechanism by which intravenous or parenteral administration of MSCs permits an auto-transplanted therapeutic cell to effectively target a specific area of pathology.

Adipose-derived regenerative cells contain endothelial progenitor cells and MSCs that assist in angiogenesis and neovascularization by the secretion of cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), placental growth factor (PGF), transforming growth factor (TGF), fibroblast growth factor (FGF-2), and angiopoietin.25

Apoptosis is defined as a programmed cell death or cell suicide, an event that is genetically controlled.35 Under normal conditions, apoptosis determines the lifespan and coordinated removal of cells. Unlike during necrosis, apoptotic cells are typically intact during their removal (phagocytosis).

See the article here:
What is VetStem Regenerative Medicine? | Why Use Adipose ...

A cell-by-cell search for cardiac stem cells has come up empty, suggesting that previous studies hinting at the existence of cardiac stem cells were mistaken. More significantly, the absence of cardiac stem cells indicates that heart muscle that is lost due to a heart attack cannot be replaced.

The sobering finding was reported by scientists based at the Hubrecht Institute, which is located in the Netherlands. The scientists, led by Hans Clevers, group leader at the Hubrecht Institute and professor of molecular genetics at the University Medical Center Utrecht, published their work this week in the Proceedings of the National Academy of Sciences.

Along with colleagues from cole Normale Suprieure de Lyon and the Francis Crick Institute London, the Hubrecht Institute scientists described how they applied the broadest and most direct definition of stem cell function in the mouse heart: the ability of a cell to replace lost tissue by cell division. In the heart, this means that any cell that can produce new heart muscle cells after a heart attack would be termed a cardiac stem cell.

In an attempt to find cardiac stem cells, the scientists generated a cell-by-cell map of all dividing cardiac cells before and after a myocardial infarction using advanced molecular and genetic technologies. Details of this work appeared in the PNAS article, which is titled, Profiling proliferative cells and their progeny in damaged murine hearts.

Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types, the articles authors indicated in a prepublication version of their paper. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of FSTL1 in cardiac fibroblasts results in postdamage cardiac rupture.

Ultimately, the researchers found no evidence for the existence of a quiescent circulating stem cell population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

Most tissues of animals and humans contain stem cells that come to the rescue upon tissue damage: they rapidly produce large numbers of daughter cells to replace lost tissue cells. Cardiac tissues, however, appear to behave differently. According to the new study, the damaged heart incorporates many types of dividing cells, but none that are capable of generating new heart muscle. In fact, many of the false leads of past studies can now be explained: cells that were previously named cardiac stem cells now turn out to produce blood vessels or immune cells, but never heart muscle. Thus, the sobering conclusion is drawn that heart stem cells do not exist.

The authors make a second important observation. Connective tissue cells (also known as fibroblasts) that are intermingled with heart muscle cells respond vigorously to a myocardial infarction by undergoing multiple cell divisions. In doing so, they produce scar tissue that replaces the lost cardiac muscle.

While this scar tissue contains no muscle and thus does not contribute to the pump function of the heart, the fibrotic scar holds together the infarcted area. Indeed, when the formation of the scar tissue is blocked, the mice succumb to acute cardiac rupture. Thus, while scar formation is generally seen as a negative outcome of myocardial infarction, the authors stress the importance of the formation of scar tissue for maintaining the integrity of the heart.

View post:
Adult Hearts Lack Cardiac Stem Cells - genengnews.com

Human life is dependent upon the hearts ability to pump forcefully and frequently enough, but heart failure signs can disturb its normal function. Most humans cannot live more than four minutes without a heartbeat or continuous blood-flow. At that time, brain cells begin to die because they lack adequately oxygenated blood-flow.

The human adult body requires, on average, 5.0 liters of re-circulated blood per minute. In the cardiology field, this metric is called the Cardiac Output, which is calculated as Stroke Volume (SV) x Heart Rate (HR). Another key metric is a patients Ejection-Fraction (EF %). A patients EF tells a cardiologist and other physicians if his or her heart is functioning normally or low normally. It is a measurement of ones heart contraction, with a normal EF range being 55-70%.

This number can also be combined with a patients heart rate to provide physicians with a baseline of a patients cardiac status. A normal range for an adult is 60-100 beats per minute, and this can be significantly higher during a normal pregnancy.

In this article:

For a cardiologist, cardiac metrics indicate if their services are required and allowthem to sign-off on pre-operative cardiac clearances. For other physicians, it tells them if the organ which they specialize in is being perfused adequately (for example, a nephrologist would be interested to know kidney perfusion). It can also indicate the degree to which decreased heart function may affect the severity or spread of disease.

When the heart fails to contract forcefully enough and its performance decreases to the point where its ability to circulate blood adequately is compromised (the EF% falls below 40%), this is considered heart failure. The clinical parameters of heart failure are clearly defined by the New York Heart Association (NYHA), which places patients in NYHA Class III & IV into the heart failure category.

An echocardiogram (often called an Echo), as opposed to an Electrocardiogram (EKG or ECG), allows technicians and physicians to visualize the beating heart. Video clips of the heart contracting are digitally recorded, and a patients EF and Cardiac Output (CO) can be measured with several diagnostic tools (Fractional Shortening via 2D or M-Mode measurements and Simpsons Method via 2D and 3D Quantification) on a cardiovascular ultrasound system.

When an experienced echo tech or cardiologist views a failing heart, it is immediately apparent. Based on my experience reading echocardiograms, I can see that the heart walls or heart muscles (myocardium) are not contracting as vigorously as they should.

For patients with a 5% EF range, any physical movement is extremely strenuous, and they can go into cardiac arrest at any moment, which is why they are usually on cardiac telemetry in a hospital setting. Most likely, a patient with 5% EF range would be awaiting a heart transplant, unless there is a medical condition preventing them from being eligible.

Once a patient falls into the heart failure range, they will be lethargic and have severe limits on activities. Other clinical manifestations of heart failure can include peripheral edema (i.e. swelling in the feet, legs, ankles, or stomach), pulmonary edema, and shortness of breath. In many cases, this can lead to depression.

In evaluating the frequency of heart failure in the U.S, statistics from the U.S. Centers for Disease Control (CDC) find that approximately 5.7 million adults are afflicted with this condition. Additionally, care for congestive heart failure costs an estimated $30.7B per year. Furthermore, the mortality rates of patients suffering from heart failure indicate its clinical severity, with 1 in 5 patients with this condition dying within a year of receiving the diagnosis.

A patient experiencing severe heart failure has limited treatment options, which are expensive, complicated, and have major lifestyle implications.

These limited options include:

Consequently, physicians need more effective weapons for treating heart failure in order to improve patients lives and reduce healthcare-related costs. CHF patients have disproportionate hospital readmission rates when compared to other major diseases.

Enter in the growing field of cardiac stem cell treatments, which introduce fundamentally new treatment options for heart failure patients. In cardiac stem cell treatments, stem cells are taken from a patients bone marrow or fat tissue in a sterile surgical procedure and injected via a catheter-wire into infarcted or poorly contracting muscular segments of the hearts main pumping chamber, the left ventricle (LV).

Over the course of a few months, the stem cells impact myocardial cells and begin to improve the contractility of the affected segments, most likely through paracrine signaling mechanisms and impacting the local microenvironment. This can bring a patients EF to low-normal or even normal levels. As a result, a patient can live a more normal life and return to many activities.

A very early clinical trial aimed at evaluating the potential and effectiveness of cardiac stem cell therapy in humans was conducted in 2006 utilizing a commercial product, VesCellTM. The parameters and results of this trial were documented in the American Heart Associations Circulation, Abstract 3682: Treatment of Patients with Severe Angina Pectoris Using Intracoronarily Injected Autologous Blood-Borne Angiogenic Cell Precursors.The subjects of this trial received an intracoronary injection of VesCellTM, an Autologous Angiogenic Cell Precursor (ACP)-based product.

The authors drew their conclusion regarding this study. VesCell therapy for chronic stable angina seems to be safe and improves anginal symptoms at 3 and 6 months. Larger studies are being initiated to evaluate the benefit of VesCell for the treatment of this and additional severe heart diseases. (Source: Tresukosol et al. Abstract 3682: Treatment of Patients with Severe Angina Pectoris Using Intracoronarily Injected Autologous Blood-Borne Angiogenic Cell Precursors. Circulation. October 31, 2006. Vol. 114, Issue Suppl 18. Link: http://circ.ahajournals.org/content/114/Suppl_18/II_786.4 )

Another early cardiac stem cell clinical trial was performed in 2009 by a Cedars-Sinai team based on technologies and discoveries made by Eduardo Marban, MD, PhD, and led by Raj Makkar, MD. In this study, they explored the safety of harvesting, expanding, and administering a patients cardiac stem cells to repair heart tissue injured by myocardial infarction.

Recently, the American College of Cardiology (ACC) also announced results of a ground-breaking clinical study to evaluate the efficacy and effectiveness of cardiac stem cell treatment for heart failure patients. As stated by Timothy Henry, M.D., Director of Cardiology at Cedars-Sinai Heart Institute and one of the studys lead authors, This is the largest double-blind, placebo-controlled stem cell trial for treatment of heart failure to be presentedBased on these positive results, we are encouraged that this is an attractive potential therapy for patients with class III and class IV heart failure.

Additionally, Dr. Charles Goldthwaite, Jr, published a whitepaper titled, Mending a Broken Heart: Stem Cells and Cardiac Repair, in which he draws the conclusion, Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types, and modes of their delivery, and the safety issues that will accompany their use.

Clearly, there is a trend toward acceptance of cardiac stem cell therapies as an emerging treatment option. Several world-renowned institutes are now conducting clinical studies involving cardiac stem cell treatment, as well as applying for intellectual property protection (patents) pertaining to the techniques required in administrating the therapies.

The key questions at this point in time appear to be:

An important whitepaper pertaining to cardiac stem cells is Ischemic Cardiomyopathy Patients Treated with Autologous Angiogenic and Cardio-Regenerative Progenitor Cells, written by Dr. Athina Kyritsis, et al. In it, the physicians describe their objective as investigating the feasibility, safety, and clinical outcome of patients with Ischemic Cardiomyopathy treated with Autologous Angiogenic and Cardio-Regenerative Progenitor cells (ACPs).

The researchers state: In numerous human trials there is evidence of improvement in the ejection fractions of Cardiomyopathy patients treated with ACPs. Animal experiments not only show improvement in cardiac function, but also engraftment and differentiation of ACPs into cardiomyocytes, as well as neo-vascularization in infarcted myocardium. In our clinical experience, the process has shown to be safe as well as effective.

The authors also found that patients treated with this approach gained increases in cardiac ejection fraction from their starting measurements, with improvements in their cardiac ejection fraction of 21 points (75% increase) at rest and 28.5 points (80% increase) at stress. As a result of these finding, the authors conclude, ACPs can improve the ejection fraction in patients with severely reduced cardiac function with benefits sustained to six months.

In the practice of medicine, the focus should be on delivering excellent care to patients. If there are cardiac stem cell treatments available, then regulatory obstacles should be removed when sufficient clinical trial evidence has been provided to indicate safety and efficacy.

Cardiologist Zannos Grekos, MD, a pioneer in cardiac stem cell therapy since 2006, points to the vastly untapped promise of related therapies, commenting Those of us that have been involved with cardiac stem cell treatment for the last 10-plus years can see the incredible potential this approach has.

As of 2017, the U.S. healthcare system is under enormous pressure to deliver affordable healthcareto a growing population of patients, especially those who are fully or partially covered under Medicare or Medicaid (many have secondary coverage). Although we are in the infancy of its development, cardiac stem cell treatments represent a potentially powerful treatment alternative to patients with heart failure symptoms.

To learn more, view the resources below.

1) Regenocyte http://www.regenocyte.com

2) Cleveland Clinic Stem Cell Therapy for Heart Disease my.clevelandclinic.org/health/articles/stem-cell-therapy-heart-disease

3) Harvard Stem Cell Institute (HSCI) hsci.harvard.edu/heart-disease-0

4) Cedars Sinai Cardiac Stem Cell Treatment http://www.cedars-sinai.edu/Patients/Programs-and-Services/Heart-Institute/Clinical-Trials/Cardiac-Stem-Cell-Research.aspx

5) Johns Hopkins Medicine Cardiac Stem Cell Treatments http://www.hopkinsmedicine.org/stem_cell_research/cell_therapy/a_new_path_for_cardiac_stem_cells.html

What do you think about heart failure signs and cardiac stem cell therapies? Share your thoughts in the comments section below.

Up Next:European Society of Cardiology (ESC) Congress Presentation Reveals Results From Pre-Clinical Study Using CardioCells Stem Cells for Acute Myocardial Infarction

Guest Post: This is a guest article by Clifford M. Thornton, a Certified Cardiovascular Technologist, experienced Echocardiographer Technician, and journalist in the cardiac and medical device fields. His articles have been published in Inventors Digest, Global Innovation Magazine, and Modern Health Talk. He is enthusiastic about progress with cardiac stem cell therapies and their role in heart failure treatment.He can be reached byphone at 267-524-7144 or by email at[emailprotected].

Editors Note This post was originally published on March 14, 2017, and has been updated for quality and relevancy.

Heart Failure Signs | Cardiac Stem Cell Therapies for Heart Failure Treatment

Excerpt from:
Heart Failure Signs | Cardiac Stem Cell Therapies: Heart ...

The old rats appeared newly invigorated after receiving their injections. As hoped, the cardiac stem cells improved heart function yet also provided additional benefits. The rats' fur fur, shaved for surgery, grew back more quickly than expected, and their chromosomal telomeres, which commonly shrink with age, lengthened.

The old rats receiving the cardiac stem cells also had increased stamina overall, exercising more than before the infusion.

"It's extremely exciting," said Dr. Eduardo Marbn, primary investigator on the research and director of the Cedars-Sinai Heart Institute. Witnessing "the systemic rejuvenating effects," he said, "it's kind of like an unexpected fountain of youth."

"We've been studying new forms of cell therapy for the heart for some 12 years now," Marbn said.

Some of this research has focused on cardiosphere-derived cells.

"They're progenitor cells from the heart itself," Marbn said. Progenitor cells are generated from stem cells and share some, but not all, of the same properties. For instance, they can differentiate into more than one kind of cell like stem cells, but unlike stem cells, progenitor cells cannot divide and reproduce indefinitely.

Since heart failure with preserved ejection fraction is similar to aging, Marbn decided to experiment on old rats, ones that suffered from a type of heart problem "that's very typical of what we find in older human beings: The heart's stiff, and it doesn't relax right, and it causes fluid to back up some," Marbn explained.

He and his team injected cardiosphere-derived cells from newborn rats into the hearts of 22-month-old rats -- that's elderly for a rat. Similar old rats received a placebo injection of saline solution. Then, Marbn and his team compared both groups to young rats that were 4 months old. After a month, they compared the rats again.

Even though the cells were injected into the heart, their effects were noticeable throughout the body, Marbn said

"The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because I'm kind of losing my hair) the animals ... regrew their fur a lot better after they'd gotten cells" compared with the placebo rats, Marbn said.

The rats that received cardiosphere-derived cells also experienced improved heart function and showed longer heart cell telomeres.

Why did it work?

The working hypothesis is that the cells secrete exosomes, tiny vesicles that "contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injury and the way genes are expressed in the tissue," Marbn said.

It is the exosomes that act on the heart and make it better as well as mediating long-distance effects on exercise capacity and hair regrowth, he explained.

Looking to the future, Marbn said he's begun to explore delivering the cardiac stem cells intravenously in a simple infusion -- instead of injecting them directly into the heart, which would be a complex procedure for a human patient -- and seeing whether the same beneficial effects occur.

Dr. Gary Gerstenblith, a professor of medicine in the cardiology division of Johns Hopkins Medicine, said the new study is "very comprehensive."

"Striking benefits are demonstrated not only from a cardiac perspective but across multiple organ systems," said Gerstenblith, who did not contribute to the new research. "The results suggest that stem cell therapies should be studied as an additional therapeutic option in the treatment of cardiac and other diseases common in the elderly."

Todd Herron, director of the University of Michigan Frankel Cardiovascular Center's Cardiovascular Regeneration Core Laboratory, said Marbn, with his previous work with cardiac stem cells, has "led the field in this area."

"The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they've seen in the past," said Herron, who played no role in the new research.

One strength of the approach here is that the researchers have taken cells "from the organ that they want to rejuvenate, so that makes it likely that the cells stay there in that tissue," Herron said.

He believes that more extensive study, beginning with larger animals and including long-term followup, is needed before this technique could be used in humans.

"We need to make sure there's no harm being done," Herron said, adding that extending the lifetime and improving quality of life amounts to "a tradeoff between the potential risk and the potential good that can be done."

Capicor hasn't announced any plans to do studies in aging, but the possibility exists.

After all, the cells have been proven "completely safe" in "over 100 human patients," so it would be possible to fast-track them into the clinic, Marbn explained: "I can't tell you that there are any plans to do that, but it could easily be done from a safety viewpoint."

Original post:
Cardiac stem cells rejuvenate rats' aging hearts ... - CNN

Stem cell, an undifferentiated cell that can divide to produce some offspring cells that continue as stem cells and some cells that are destined to differentiate (become specialized). Stem cells are an ongoing source of the differentiated cells that make up the tissues and organs of animals and plants. There is great interest in stem cells because they have potential in the development of therapies for replacing defective or damaged cells resulting from a variety of disorders and injuries, such as Parkinson disease, heart disease, and diabetes. There are two major types of stem cells: embryonic stem cells and adult stem cells, which are also called tissue stem cells.

Read More on This Topic

cardiovascular disease: Cardiac stem cells

Cardiac stem cells, which have the ability to differentiate (specialize) into mature heart cells and therefore could be used to repair damaged or diseased heart tissue, have garnered significant interest in the development of treatments for heart disease and cardiac defects. Cardiac stem

Embryonic stem cells (often referred to as ES cells) are stem cells that are derived from the inner cell mass of a mammalian embryo at a very early stage of development, when it is composed of a hollow sphere of dividing cells (a blastocyst). Embryonic stem cells from human embryos and from embryos of certain other mammalian species can be grown in tissue culture.

The most-studied embryonic stem cells are mouse embryonic stem cells, which were first reported in 1981. This type of stem cell can be cultured indefinitely in the presence of leukemia inhibitory factor (LIF), a glycoprotein cytokine. If cultured mouse embryonic stem cells are injected into an early mouse embryo at the blastocyst stage, they will become integrated into the embryo and produce cells that differentiate into most or all of the tissue types that subsequently develop. This ability to repopulate mouse embryos is the key defining feature of embryonic stem cells, and because of it they are considered to be pluripotentthat is, able to give rise to any cell type of the adult organism. If the embryonic stem cells are kept in culture in the absence of LIF, they will differentiate into embryoid bodies, which somewhat resemble early mouse embryos at the egg-cylinder stage, with embryonic stem cells inside an outer layer of endoderm. If embryonic stem cells are grafted into an adult mouse, they will develop into a type of tumour called a teratoma, which contains a variety of differentiated tissue types.

Mouse embryonic stem cells are widely used to create genetically modified mice. This is done by introducing new genes into embryonic stem cells in tissue culture, selecting the particular genetic variant that is desired, and then inserting the genetically modified cells into mouse embryos. The resulting chimeric mice are composed partly of host cells and partly of the donor embryonic stem cells. As long as some of the chimeric mice have germ cells (sperm or eggs) that have been derived from the embryonic stem cells, it is possible to breed a line of mice that have the same genetic constitution as the embryonic stem cells and therefore incorporate the genetic modification that was made in vitro. This method has been used to produce thousands of new genetic lines of mice. In many such genetic lines, individual genes have been ablated in order to study their biological function; in others, genes have been introduced that have the same mutations that are found in various human genetic diseases. These mouse models for human disease are used in research to investigate both the pathology of the disease and new methods for therapy.

Extensive experience with mouse embryonic stem cells made it possible for scientists to grow human embryonic stem cells from early human embryos, and the first human stem cell line was created in 1998. Human embryonic stem cells are in many respects similar to mouse embryonic stem cells, but they do not require LIF for their maintenance. The human embryonic stem cells form a wide variety of differentiated tissues in vitro, and they form teratomas when grafted into immunosuppressed mice. It is not known whether the cells can colonize all the tissues of a human embryo, but it is presumed from their other properties that they are indeed pluripotent cells, and they therefore are regarded as a possible source of differentiated cells for cell therapythe replacement of a patients defective cell type with healthy cells. Large quantities of cells, such as dopamine-secreting neurons for the treatment of Parkinson disease and insulin-secreting pancreatic beta cells for the treatment of diabetes, could be produced from embryonic stem cells for cell transplantation. Cells for this purpose have previously been obtainable only from sources in very limited supply, such as the pancreatic beta cells obtained from the cadavers of human organ donors.

The use of human embryonic stem cells evokes ethical concerns, because the blastocyst-stage embryos are destroyed in the process of obtaining the stem cells. The embryos from which stem cells have been obtained are produced through in vitro fertilization, and people who consider preimplantation human embryos to be human beings generally believe that such work is morally wrong. Others accept it because they regard the blastocysts to be simply balls of cells, and human cells used in laboratories have not previously been accorded any special moral or legal status. Moreover, it is known that none of the cells of the inner cell mass are exclusively destined to become part of the embryo itselfall of the cells contribute some or all of their cell offspring to the placenta, which also has not been accorded any special legal status. The divergence of views on this issue is illustrated by the fact that the use of human embryonic stem cells is allowed in some countries and prohibited in others.

In 2009 the U.S. Food and Drug Administration approved the first clinical trial designed to test a human embryonic stem cell-based therapy, but the trial was halted in late 2011 because of a lack of funding and a change in lead American biotech company Gerons business directives. The therapy to be tested was known as GRNOPC1, which consisted of progenitor cells (partially differentiated cells) that, once inside the body, matured into neural cells known as oligodendrocytes. The oligodendrocyte progenitors of GRNOPC1 were derived from human embryonic stem cells. The therapy was designed for the restoration of nerve function in persons suffering from acute spinal cord injury.

Embryonic germ (EG) cells, derived from primordial germ cells found in the gonadal ridge of a late embryo, have many of the properties of embryonic stem cells. The primordial germ cells in an embryo develop into stem cells that in an adult generate the reproductive gametes (sperm or eggs). In mice and humans it is possible to grow embryonic germ cells in tissue culture with the appropriate growth factorsnamely, LIF and another cytokine called fibroblast growth factor.

Some tissues in the adult body, such as the epidermis of the skin, the lining of the small intestine, and bone marrow, undergo continuous cellular turnover. They contain stem cells, which persist indefinitely, and a much larger number of transit amplifying cells, which arise from the stem cells and divide a finite number of times until they become differentiated. The stem cells exist in niches formed by other cells, which secrete substances that keep the stem cells alive and active. Some types of tissue, such as liver tissue, show minimal cell division or undergo cell division only when injured. In such tissues there is probably no special stem-cell population, and any cell can participate in tissue regeneration when required.

The epidermis of the skin contains layers of cells called keratinocytes. Only the basal layer, next to the dermis, contains cells that divide. A number of these cells are stem cells, but the majority are transit amplifying cells. The keratinocytes slowly move outward through the epidermis as they mature, and they eventually die and are sloughed off at the surface of the skin. The epithelium of the small intestine forms projections called villi, which are interspersed with small pits called crypts. The dividing cells are located in the crypts, with the stem cells lying near the base of each crypt. Cells are continuously produced in the crypts, migrate onto the villi, and are eventually shed into the lumen of the intestine. As they migrate, they differentiate into the cell types characteristic of the intestinal epithelium.

Bone marrow contains cells called hematopoietic stem cells, which generate all the cell types of the blood and the immune system. Hematopoietic stem cells are also found in small numbers in peripheral blood and in larger numbers in umbilical cord blood. In bone marrow, hematopoietic stem cells are anchored to osteoblasts of the trabecular bone and to blood vessels. They generate progeny that can become lymphocytes, granulocytes, red blood cells, and certain other cell types, depending on the balance of growth factors in their immediate environment.

Work with experimental animals has shown that transplants of hematopoietic stem cells can occasionally colonize other tissues, with the transplanted cells becoming neurons, muscle cells, or epithelia. The degree to which transplanted hematopoietic stem cells are able to colonize other tissues is exceedingly small. Despite this, the use of hematopoietic stem cell transplants is being explored for conditions such as heart disease or autoimmune disorders. It is an especially attractive option for those opposed to the use of embryonic stem cells.

Bone marrow transplants (also known as bone marrow grafts) represent a type of stem cell therapy that is in common use. They are used to allow cancer patients to survive otherwise lethal doses of radiation therapy or chemotherapy that destroy the stem cells in bone marrow. For this procedure, the patients own marrow is harvested before the cancer treatment and is then reinfused into the body after treatment. The hematopoietic stem cells of the transplant colonize the damaged marrow and eventually repopulate the blood and the immune system with functional cells. Bone marrow transplants are also often carried out between individuals (allograft). In this case the grafted marrow has some beneficial antitumour effect. Risks associated with bone marrow allografts include rejection of the graft by the patients immune system and reaction of immune cells of the graft against the patients tissues (graft-versus-host disease).

Bone marrow is a source for mesenchymal stem cells (sometimes called marrow stromal cells, or MSCs), which are precursors to non-hematopoietic stem cells that have the potential to differentiate into several different types of cells, including cells that form bone, muscle, and connective tissue. In cell cultures, bone-marrow-derived mesenchymal stem cells demonstrate pluripotency when exposed to substances that influence cell differentiation. Harnessing these pluripotent properties has become highly valuable in the generation of transplantable tissues and organs. In 2008 scientists used mesenchymal stem cells to bioengineer a section of trachea that was transplanted into a woman whose upper airway had been severely damaged by tuberculosis. The stem cells were derived from the womans bone marrow, cultured in a laboratory, and used for tissue engineering. In the engineering process, a donor trachea was stripped of its interior and exterior cell linings, leaving behind a trachea scaffold of connective tissue. The stem cells derived from the recipient were then used to recolonize the interior of the scaffold, and normal epithelial cells, also isolated from the recipient, were used to recolonize the exterior of the trachea. The use of the recipients own cells to populate the trachea scaffold prevented immune rejection and eliminated the need for immunosuppression therapy. The transplant, which was successful, was the first of its kind.

Research has shown that there are also stem cells in the brain. In mammals very few new neurons are formed after birth, but some neurons in the olfactory bulbs and in the hippocampus are continually being formed. These neurons arise from neural stem cells, which can be cultured in vitro in the form of neurospheressmall cell clusters that contain stem cells and some of their progeny. This type of stem cell is being studied for use in cell therapy to treat Parkinson disease and other forms of neurodegeneration or traumatic damage to the central nervous system.

Following experiments in animals, including those used to create Dolly the sheep, there has been much discussion about the use of somatic cell nuclear transfer (SCNT) to create pluripotent human cells. In SCNT the nucleus of a somatic cell (a fully differentiated cell, excluding germ cells), which contains the majority of the cells DNA (deoxyribonucleic acid), is removed and transferred into an unfertilized egg cell that has had its own nuclear DNA removed. The egg cell is grown in culture until it reaches the blastocyst stage. The inner cell mass is then removed from the egg, and the cells are grown in culture to form an embryonic stem cell line (generations of cells originating from the same group of parent cells). These cells can then be stimulated to differentiate into various types of cells needed for transplantation. Since these cells would be genetically identical to the original donor, they could be used to treat the donor with no problems of immune rejection. Scientists generated human embryonic stem cells successfully from SCNT human embryos for the first time in 2013.

While promising, the generation and use of SCNT-derived embryonic stem cells is controversial for several reasons. One is that SCNT can require more than a dozen eggs before one egg successfully produces embryonic stem cells. Human eggs are in short supply, and there are many legal and ethical problems associated with egg donation. There are also unknown risks involved with transplanting SCNT-derived stem cells into humans, because the mechanism by which the unfertilized egg is able to reprogram the nuclear DNA of a differentiated cell is not entirely understood. In addition, SCNT is commonly used to produce clones of animals (such as Dolly). Although the cloning of humans is currently illegal throughout the world, the egg cell that contains nuclear DNA from an adult cell could in theory be implanted into a womans uterus and come to term as an actual cloned human. Thus, there exists strong opposition among some groups to the use of SCNT to generate human embryonic stem cells.

Due to the ethical and moral issues surrounding the use of embryonic stem cells, scientists have searched for ways to reprogram adult somatic cells. Studies of cell fusion, in which differentiated adult somatic cells grown in culture with embryonic stem cells fuse with the stem cells and acquire embryonic stem-cell-like properties, led to the idea that specific genes could reprogram differentiated adult cells. An advantage of cell fusion is that it relies on existing embryonic stem cells instead of eggs. However, fused cells stimulate an immune response when transplanted into humans, which leads to transplant rejection. As a result, research has become increasingly focused on the genes and proteins capable of reprogramming adult cells to a pluripotent state. In order to make adult cells pluripotent without fusing them to embryonic stem cells, regulatory genes that induce pluripotency must be introduced into the nuclei of adult cells. To do this, adult cells are grown in cell culture, and specific combinations of regulatory genes are inserted into retroviruses (viruses that convert RNA [ribonucleic acid] into DNA), which are then introduced to the culture medium. The retroviruses transport the RNA of the regulatory genes into the nuclei of the adult cells, where the genes are then incorporated into the DNA of the cells. About 1 out of every 10,000 cells acquires embryonic stem cell properties. Although the mechanism is still uncertain, it is clear that some of the genes confer embryonic stem cell properties by means of the regulation of numerous other genes. Adult cells that become reprogrammed in this way are known as induced pluripotent stem cells (iPS).

Similar to embryonic stem cells, induced pluripotent stem cells can be stimulated to differentiate into select types of cells that could in principle be used for disease-specific treatments. In addition, the generation of induced pluripotent stem cells from the adult cells of patients affected by genetic diseases can be used to model the diseases in the laboratory. For example, in 2008 researchers isolated skin cells from a child with an inherited neurological disease called spinal muscular atrophy and then reprogrammed these cells into induced pluripotent stem cells. The reprogrammed cells retained the disease genotype of the adult cells and were stimulated to differentiate into motor neurons that displayed functional insufficiencies associated with spinal muscular atrophy. By recapitulating the disease in the laboratory, scientists were able to study closely the cellular changes that occurred as the disease progressed. Such models promise not only to improve scientists understanding of genetic diseases but also to facilitate the development of new therapeutic strategies tailored to each type of genetic disease.

In 2009 scientists successfully generated retinal cells of the human eye by reprogramming adult skin cells. This advance enabled detailed investigation of the embryonic development of retinal cells and opened avenues for the generation of novel therapies for eye diseases. The production of retinal cells from reprogrammed skin cells may be particularly useful in the treatment of retinitis pigmentosa, which is characterized by the progressive degeneration of the retina, eventually leading to night blindness and other complications of vision. Although retinal cells also have been produced from human embryonic stem cells, induced pluripotency represents a less controversial approach. Scientists have also explored the possibility of combining induced pluripotent stem cell technology with gene therapy, which would be of value particularly for patients with genetic disease who would benefit from autologous transplantation.

Researchers have also been able to generate cardiac stem cells for the treatment of certain forms of heart disease through the process of dedifferentiation, in which mature heart cells are stimulated to revert to stem cells. The first attempt at the transplantation of autologous cardiac stem cells was performed in 2009, when doctors isolated heart tissue from a patient, cultured the tissue in a laboratory, stimulated cell dedifferentiation, and then reinfused the cardiac stem cells directly into the patients heart. A similar study involving 14 patients who underwent cardiac bypass surgery followed by cardiac stem cell transplantation was reported in 2011. More than three months after stem cell transplantation, the patients experienced a slight but detectable improvement in heart function.

Patient-specific induced pluripotent stem cells and dedifferentiated cells are highly valuable in terms of their therapeutic applications because they are unlikely to be rejected by the immune system. However, before induced pluripotent stem cells can be used to treat human diseases, researchers must find a way to introduce the active reprogramming genes without using retroviruses, which can cause diseases such as leukemia in humans. A possible alternative to the use of retroviruses to transport regulatory genes into the nuclei of adult cells is the use of plasmids, which are less tumourigenic than viruses.

Here is the original post:
stem cell | Definition, Types, Uses, Research, & Facts ...

Cardiac stem cell research has a turbulent history. Studies revealing the presence of regenerative progenitors in adult rodents hearts formed the basis of numerous clinical trials, but several experiments have cast doubt on these cells ability to produce new tissue. Some scientists are now lauding the results of a report published in April in Circulation as undeniable evidence against the idea that resident stem cells can give rise to new cardiomyocytes.

The concept of [many] clinical trials arose from the basic science in labs of a few individuals more than 15 years ago, and that basic science is whats now being called into question, says Jeffery Molkentin, a cardiovascular biologist at Cincinnati Childrens Hospital who penned an editorial about the latest work.

The first evidence supporting the notion of cardiac stem cells in adults emerged in the early 2000s, when researchers reported that cells derived from bone marrow or adult heart expressing the protein c-kit could give rise to new muscle tissue when injected into damaged myocardium in rodents. These studies caused some controversy right from the start, Molkentin says. The main reason that this struck a raw nerve with people is because we already know that heart, in human patients, doesnt regenerate itself after an infarct.

Early skepticism arose in 2004, when two separate groups of researchers published back-to-back papers refuting the claims that bone marrowderived c-kit cells could regenerate damaged heart tissue. Still, the concept of endogenous cardiac stem cells remained a mainstream idea until Molkentin and his colleagues published a study in 2014 reporting that c-kit cells in the adult mouse heart almost never produced new cardiomyocytes, says Bin Zhou, a cell biologist at the Chinese Academy of Sciences and a coauthor of the new study.

Although Molkentins findings were replicated shortly afterwards by two independent groups (including Zhous), some researchers held fast to the idea that cardiac progenitors could regenerate injured heart tissue. Earlier this year, a team of researchersincluding Bernardo Nadal-Ginard and Daniele Torella of Magna Graecia University in Italy and several other scientists who conducted the early work on c-kit cellspublished a paper reporting the flaws in the cell lineage tracing technique employed by Molkentin, Zhou, and their colleagues. For example, they noted that the method, which involved tagging c-kitexpressing cells and their progeny with a fluorescent marker, compromised the gene required to express the c-kit protein, impairing the progenitors regenerative abilities.

In the new Circulationstudy, Zhou and his colleagues used a different approach to examine endogenous stem cell populations in mice. Instead of tagging c-kit cells, the team applied a technique that would fluorescently label nonmyocytes and newly generated muscle cells a different color from existing myocytes. This method allowed the researchers to investigate all proposed stem cell populations, rather than specifically addressing c-kit cells. We wanted to ask the broader question of whether there are any stem cells in the adult heart, Zhou says.

These experiments revealed that, while nonmyocytes generate cardiomyocytes in mouse embryos, they do not give rise to new muscle cells in adult rodents hearts. The results also address the concerns raised about c-kit lineage tracing, Zhou tells The Scientist. We think our system can conclude that nonmyocytes cannot become myocytes in adults in homeostasis and after injury.

Torella says that hes not convinced by Zhous evidence. The main issue, he explains, is that the researchers did not explicitly test whether cardiac stem cells were indeed labeled as nonmyocytes to ensure that they were not inadvertently tagging them as myocytes instead.

Molkentin disagrees with this critique, stating that the only way the system would label a myocyte progenitor as a myocyte is if it was no longer a true stem cell, but instead an immature myocyte. Zhous group uses an exhausting and very rigorous genetic approach, he adds. My opinion is that we need to go back to the bench and conduct additional research to truly understand the mechanisms at play to better inform how we design the next generation of clinical trials.

Other scientists note that stem cells may not need to become new myocytes to help repair the injured heart. According to Phillip Yang, a cardiologist at Stanford University who did not take part in the work, many scientists now agree that stem cells are not regenerating damaged cardiomyocytes. Instead, he explains, a growing body of research now supports an alternative theory, which posits that progenitor cells secrete small molecules called paracrine factors that help repair injured heart cells. (Yang is involved in several stem cell clinical trials).

When you inject these stem cells, its pretty incontrovertible that they help heart function in a mouse injury model, Yang says. But the truth is, most of these cells are dead upon arrival [to the site of injury]. So the question is: Why is heart function still improving if these cells are dying?

Y. Li et al., Genetic lineage tracing of nonmyocyte population by dual recombinases, Circulation, 138:793-805, 2018.

Read more here:
Adult Cardiac Stem Cells Don't Exist: Study | The ...

There was a very sad example of this in the last decade.There's a wonderful drug, and a class of drugs actually,but the particular drug was Vioxx, andfor people who were suffering from severe arthritis pain,the drug was an absolute lifesaver,but unfortunately, for another subset of those people,they suffered pretty severe heart side effects,and for a subset of those people, the side effects wereso severe, the cardiac side effects, that they were fatal.But imagine a different scenario,where we could have had an array, a genetically diverse array,of cardiac cells, and we could have actually testedthat drug, Vioxx, in petri dishes, and figured out,well, okay, people with this genetic type are going to havecardiac side effects, people with these genetic subgroupsor genetic shoes sizes, about 25,000 of them,are not going to have any problems.The people for whom it was a lifesavercould have still taken their medicine.The people for whom it was a disaster, or fatal,would never have been given it, andyou can imagine a very different outcome for the company,who had to withdraw the drug.

Read the original here:
Susan Solomon: The promise of research with stem cells ...

Stem cell therapy can be described as a means or process by which stem cells are used for the prevention, treatment or the cure of diseases. Stem cells are a special kind of cells that have features other types of cells dont have. As an illustration, stem cells are capable of proliferation. This implies that they can develop into any type of cell, and grow to start performing the functions of the tissue. In addition, they can regenerate. This means they can multiply themselves. This is most important when a new tissue has to be formed. Also, they modulate immune reactions. This has made them useful for the treatment of autoimmune diseases, especially those that affect the musculoskeletal system such as rheumatoid arthritis, systemic lupus erythematosus and so on. Stem cells can be derrived from different sources. They can be extracted from the body, and in some specific parts of the body. This includes the blood, bone marrow, umbilical cord in newborns, adipose tissue, and from embryos. There are 2 main types of stem cell transplant. These are autologous stem cell transplant, and allogeneic stem cell transplant. The autologous stem cell transplant means that stem cells are extracted from the patient, processed, and then transplanted back to the patient, for therapeutic purposes. On the other hand, allogeneic stem cell transplant means the transplant of stem cells or from another individual, known as the donor, to another person, or recipient. Some treatments must be given to the receiver to prevent any cases of rejections, and other complications. The autologous is usually the most preferred type of transplant because of its almost zero side effects. Below are some of the stem cell treatments. Our goal is to provide education, research and an opportunity to connect with Stem Cell Doctors, as well as provide stem cell reviews

Adipose Stem Cell TreatmentsAdipose stem cell treatment is one of the most commonly used. This is because large quantities of stem cells can be derrived from them. According to statistics, the number of stem cells in adipose tissue are usually hundreds of times higher than what can be obtained from other sources, such as the bone marrow stem cells. Adipose stem cells have taken the center stage in the world of stem cell therapy. Apart from the ease that comes with the harvesting of these cells from the adipose tissue, they also have some special features, that separates them from other types of cells. Adipose stem cells are capable of regulating and modulating the immune system. This includes immune suppression, which is important for the treatment of autoimmune diseases. In addition, adipose stem cells can differentiate to form other types of cells. Some of them include the bone forming cells, cardiomyocytes, and cells of the nervous system.

This process can be divided into four parts. These are

Stem cell joint injection is fast becoming the new treatment of joint diseases. Stem cells derived from bone marrow, adipose and mesenchymal stem cells are the most commonly used. The stem cells are injected into the joints, and they proceed to repair and replace the damaged tissues. The cells also modulate the inflammatory process going on. Overall, stem cell joint injections significantly reduce the recovery time of patients and also eliminates pain and risks associated with surgery. Examples of diseases where this treatment is used include osteoarthritis, rheumatoid arthritis, and so on. Researchers and physicians have rated this procedure to be the future of joint therapy.

Losing a tooth as a kid isnt news because youd eventually grow them back, but losing one as an adult isnt a pleasant experience. Youd have to go through the pains of getting a replacement from your dentist. Apart from the cost of these procedures, the pain and number of days youd have to stay at home nursing the pain is also a problem. Nevertheless, there are great teeth replacement therapies available for all kinds of dental problems. Although there are already good dental treatment methods, stem cell therapy might soon become the future of dental procedures. Currently, a lot of research is being done on how stem cells can be used to develop teeth naturally, especially in patients with dental problems. The aim of the project is to develop a method whereby peoples stem cells are used in regenerating their own teeth and within the shortest time possible. Some of the benefits of the stem cell tooth would be:

The quality of life of those that underwent serious procedures, especially those that had an allogeneic hematopoietic stem cell transplantation done was studied. It was discovered that this set of people had to cope with some psychological problems, even years after the procedure. In addition, allogeneic stem cell transplantation often comes with some side effects. However, this a small price to pay, considering that the adverse effects are not usually life-threatening. Also theses types of procedures are used for severe disorders or even terminal diseases. On the other hand, autologous stem cell transplantation bears the minimum to no side effects. Patients do have a great quality of life, both in the short term and in the long term.

This is one of the many uses of stem cells. The stem cell gun is a device that is used in treating people with wounds or burns. This is done by simply triggering it, and it sprays stem cells on the affected part. This kind of treatment is crucial for victims of a severe burn. Usually, people affected by severe burns would have to endure excruciating pain. The process of recovery is usually long, which might vary from weeks to months, depending on the severity of the burn. Even after treatment, most patients are left with scars forever. However, the stem cell gun eliminates these problems, the skin can be grown back in just a matter of days. The new skin also grows evenly and blends perfectly with the other part of the body. This process is also without the scars that are usually associated with the traditional burns therapy. The stem cell gun is without any side effects.

There is one company that focuses on the production of stem cell supplements. These stem cells are usually natural ingredients that increase the development of stem cells, and also keeps them healthy. The purpose of the stem cell supplements is to help reduce the aging process and make people look younger. These supplements work by replacing the dead or repairing the damaged tissues of the body. There have been a lot of testimonials to the efficacy of these supplements.

It is the goal of researchers to make stem cell therapy a good alternative for the millions of patients suffering from cardiac-related diseases. According to some experiments carried out in animals, stem cells were injected into the ones affected by heart diseases. A large percentage of them showed great improvement, even within just a few weeks. However, when the trial was carried out in humans, some stem cells went ahead to develop into heart muscles, but overall, the heart function was generally improved. The reason for the improvement has been attributed to the formation of new vessels in the heart. The topic that has generated a lot of arguments have been what type of cells should be used in the treatment of heart disorders. Stem cells extracted from the bone marrow, embryo have been in use, although bone marrow stem cells are the most commonly used. Stem cells extracted from bone marrow can differentiate into cardiac cells, while studies have shown that other stem cells cannot do the same. Even though the stem cell therapy has a lot of potential in the future, more research and studies have to be done to make that a reality.

The use of stem cells for the treatment of hair loss has increased significantly. This can be attributed to the discovery of stem cells in bone marrow, adipose cells, umbilical cord, and so on. Stem cells are extracted from the patient, through any of the sources listed above. Adipose tissue stem cells are usually the most convenient in this scenario, as they do not require any special extraction procedure. Adipose tissue is harvested from the abdominal area. The stem cells are then isolated from the other cells through a process known as centrifugation. The stem cells are then activated and are now ready for use. The isolated stem cells are then introduced into the scalp, under local anesthesia. The entire process takes about three hours. Patients are free to go home, after the procedure. Patients would begin to see improvements in just a few months, however, this depends largely on the patients ability to heal. Every patient has a different outcome.

Human umbilical stem cells are cells extracted from the umbilical cord of a healthy baby, shortly after birth. Umbilical cord tissue is abundant in stem cells, and the stem cells can differentiate into many types of cells such as red blood cells, white blood cells, and platelets. They are also capable of differentiating into non-blood cells such as muscle cells, cartilage cells and so on. These cells are usually preferred because its' extraction is minimally non invasive. It also is nearly painless. It also has zero risks of rejecting, as it does not require any form of matching or typing.Human umbilical stem cell injections are used for the treatment of spinal cord injuries. A trial was done on twenty-five patients that had late-stage spinal cord injuries. They were placed on human umbilical stem cell therapy, while another set of 25 patients were simultaneously placed on the usual rehabilitation therapy. The two groups were studied for the next twelve months. The results of the trial showed that those people placed on stem cell therapy by administering the human umbilical cell tissue injections had a significant recovery, as compared to the other group that underwent the traditional rehabilitation therapy. It was concluded that human umbilical tissue injections applied close to the injured part gives the best outcomes.

Stem cell therapy has been used for the treatment of many types diseases. This ranges from terminal illnesses such as cancer, joint diseases such as arthritis, and also autoimmune diseases. Stem cell therapy is often a better alternative to most traditional therapy today. This is because stem cell procedure is minimally invasive when compared to chemotherapy and so on. It harnesses the bodys own ability to heal. The stem cells are extracted from other parts of the body and then transplanted to other parts of the body, where they would repair and maintain the tissues. They also perform the function of modulating the immune system, which makes them important for the treatment of autoimmune diseases. Below are some of the diseases that stem cell therapies have been used successfully:

A stem cell bank can be described as a facility where stem cells are stored for future purposes. These are mostly amniotic stem cells, which are derived from the amnion fluid. Umbilical cord stem cells are also equally important as it is rich in stem cells and can be used for the treatment of many diseases. Examples of these diseases include cancer, blood disorders, autoimmune diseases, musculoskeletal diseases and so on. According to statistics, umbilical stem cells can be used for the treatment of over eighty diseases. Storing your stem cells should be seen as an investment in your health for future sake. Parents do have the option of either throwing away their babys umbilical cord or donating it to stem cell banks.

The adipose tissue contains a lot of stem cells, that has the ability to transform into other cells such as muscle, cartilage, neural cells. They are also important for the treatment of some cardiovascular diseases. This is what makes it important for people to want to store their stem cells. The future health benefit is huge. The only way adults can store their stem cells in sufficient amounts is to extract the stem cells from their fat tissues. This process is usually painless and fast. Although, the extraction might have to be done between 3 to 5 times before the needed quantity is gotten. People that missed the opportunity to store their stem cells, using their cord cells, can now store it using their own adipose tissues. This can be used at any point in time.

Side effects often accompany every kind of treatment. However, this depends largely on the individual. While patients might present with side effects, some other people wouldnt. Whether a patient will present with adverse effects, depends on the following factors;

Some of the common side effects of stem cell transplant are;

Stem cell treatment has been largely successful so far, however, more studies and research needs to be done. Stem cell therapy could be the future.

Stem cells are unique cells that have some special features such as self-regeneration, tissue repair, and modulation of the immune system. These are the features that are employed in the treatment of diseases.

Our doctors are certified by iSTEMCELL but operate as part of a medical group or as independent business owners and as such are free to charge what the feel to be the right fit for their practice and clients. We have seen Stem Cell Treatment costs range from $3500 upwards of $30,000 depending on the condition and protocol required for intended results. Find the Best Stem Cell Doctor Near me If you are interested in saving money, try our STEM CELL COUPON!

Travel Medcations are becoming very popular around the globe for several reasons but not for what one might think. It is not about traveling to Mexico to save money, but to get procedures or protocols that are not yet available in your home country. Many procedures are started in your home country, then the tissue is set to the tissue lab where it is then grown in a process to maximize live cells, then sent to a hospital in Mexico designed to treat or provide different therapies for different conditions. If you're ready to take a medical vacation call 972-800-6670 for our"WHITE GLOVE" service.

Chen, C. and Hou, J. (2016). Mesenchymal stem cell-based therapy in kidney transplantation. Stem Cell Research & Therapy, 7(1).

Donnelly, A., Johar, S., OBrien, T. and Tuan, R. (2010). Welcome to Stem Cell Research & Therapy. Stem Cell Research & Therapy, 1(1), p.1.

Groothuis, S. (2015). Changes in Stem Cell Research. Stem Cell Research, 14(1), p.130.

Rao, M. (2012). Stem cells and regenerative medicine. Stem Cell Research & Therapy, 3(4), p.27.

Vunjak-Novakovic, G. (2013). Physical influences on stem cells. Stem Cell Research & Therapy, 4(6), p.153.

Continued here:
Stem Cell Therapy and Stem Cell Injection Provider Finder ...

Charles A. Goldthwaite, Jr., Ph.D.

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic.1 In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined. According to data from the 19992002 National Health and Nutrition Examination Survey (NHANES), CVD caused approximately 1.4 million deaths (38.0 percent of all deaths) in the U.S. in 2002. Nearly 2600 Americans die of CVD each day, roughly one death every 34 seconds. Moreover, within a year of diagnosis, one in five patients with CHF will die. CVD also creates a growing economic burden; the total health care cost of CVD in 2005 was estimated at $393.5 billion dollars.

Given the aging of the U.S. population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes,2,3 CVD will continue to be a significant health concern well into the 21st century. However, improvements in the acute treatment of heart attacks and an increasing arsenal of drugs have facilitated survival. In the U.S. alone, an estimated 7.1 million people have survived a heart attack, while 4.9 million live with CHF.1 These trends suggest an unmet need for therapies to regenerate or repair damaged cardiac tissue.

Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning (see Figure 6.1), an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure. However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.5 Current pharmacologic interventions for heart disease, including beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, and surgical treatment options, such as changing the shape of the left ventricle and implanting assistive devices such as pacemakers or defibrillators, do not restore function to damaged tissue. Moreover, while implantation of mechanical ventricular assist devices can provide long-term improvement in heart function, complications such as infection and blood clots remain problematic.6 Although heart transplantation offers a viable option to replace damaged myocardium in selected individuals, organ availability and transplant rejection complications limit the widespread practical use of this approach.

Figure 6.1. Normal vs. Infarcted Heart. The left ventricle has a thick muscular wall, shown in cross-section in A. After a myocardial infarction (heart attack), heart muscle cells in the left ventricle are deprived of oxygen and die (B), eventually causing the ventricular wall to become thinner (C).

2007 Terese Winslow

The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. All have been tested in mouse or rat models, and some have been tested in large animal models such as pigs. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.

However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials.7 Some patients who have received stem cells for myocardial repair have reduced cardiac blood flow (myocardial ischemia), while others have more pronounced congestive heart failure and still others are recovering from heart attacks. In some cases, the patient's underlying condition influences the way that the stem cells are delivered to his/her heart (see the section, quot;Methods of Cell Deliveryquot; for details). Even among patients undergoing comparable procedures, the clinical study design can affect the reporting of results. Some studies have focused on safety issues and adverse effects of the transplantation procedures; others have assessed improvements in ventricular function or the delivery of arterial blood. Furthermore, no published trial has directly compared two or more stem cell types, and the transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic (i.e., originating from another person) in origin. Finally, most of these trials use unlabeled cells, making it difficult for investigators to follow the cells' course through the body after transplantation (see the section quot;Considerations for Using These Stem Cells in the Clinical Settingquot; at the end of this article for more details).

Despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising. This article will review the research supporting each of the aforementioned cell types as potential source materials for myocardial regeneration and will conclude with a discussion of general issues that relate to their clinical application.

In 2001, Menasche, et.al. described the successful implantation of autologous skeletal myoblasts (cells that divide to repair and/or increase the size of voluntary muscles) into the post-infarction scar of a patient with severe ischemic heart failure who was undergoing coronary artery bypass surgery.8 Following the procedure, the researchers used imaging techniques to observe the heart's muscular wall and to assess its ability to beat. When they examined patients 5 months after treatment, they concluded that treated hearts pumped blood more efficiently and seemed to demonstrate improved tissue health. This case study suggested that stem cells may represent a viable resource for treating ischemic heart failure, spawning several dozen clinical studies of stem cell therapy for cardiac repair (see Boyle, et.al.7 for a complete list) and inspiring the development of Phase I and Phase II clinical trials. These trials have revealed the complexity of using stem cells for cardiac repair, and considerations for using stem cells in the clinical setting are discussed in a subsequent section of this report.

The mechanism by which stem cells promote cardiac repair remains controversial, and it is likely that the cells regenerate myocardium through several pathways. Initially, scientists believed that transplanted cells differentiated into cardiac cells, blood vessels, or other cells damaged by CVD.911 However, this model has been recently supplanted by the idea that transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate quot;residentquot; cardiac stem cells to repair damage.1214 Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar15 and the fusion of donor cells with host cardiomyocytes,16 have also been proposed.

Regardless of which mechanism(s) will ultimately prove to be the most significant in stem-cell mediated cardiac repair, cells must be successfully delivered to the site of injury to maximize the restored function. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. These methods can be used in patients whose blood flow has been restored to their hearts after a heart attack, provided that they do not have additional cardiac dysfunction that results in total occlusion or poor arterial flow.12, 17 Of these two methods, intracoronary infusion offers the advantage of directed local delivery, thereby increasing the number of cells that reach the target tissue relative to the number that will home to the heart once they have been placed in the circulation. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients. This endomyocardial injection may be carried out either via a catheter or during open-heart surgery.18

To determine the ideal site to inject stem cells, doctors use mapping or direct visualization to identify the locations of scars and viable cardiac tissue. Despite improvements in delivery efficiency, however, the success of these methods remains limited by the death of the transplanted cells; as many as 90% of transplanted cells die shortly after implantation as a result of physical stress, myocardial inflammation, and myocardial hypoxia.4 Timing of delivery may slow the rate of deterioration of tissue function, although this issue remains a hurdle for therapeutic approaches.

Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. A brief review of work to date and specific considerations for the application of various cell types will be discussed in the following sections.

Because ES cells are pluripotent, they can potentially give rise to the variety of cell types that are instrumental in regenerating damaged myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells. To this end, mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro19 and in vivo,20,21 and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes.2224 Moreover, ES cells that were transplanted into ischemically-injured myocardium in rats differentiated into normal myocardial cells that remained viable for up to four months,25 suggesting that these cells may be candidates for regenerative therapy in humans.

However, several key hurdles must be overcome before human ES cells can be used for clinical applications. Foremost, ethical issues related to embryo access currently limit the avenues of investigation. In addition, human ES cells must go through rigorous testing and purification procedures before the cells can be used as sources to regenerate tissue. First, researchers must verify that their putative ES cells are pluripotent. To prove that they have established a human ES cell line, researchers inject the cells into immunocompromised mice; i.e., mice that have a dysfunctional immune system. Because the injected cells cannot be destroyed by the mouse's immune system, they survive and proliferate. Under these conditions, pluripotent cells will form a teratoma, a multi-layered, benign tumor that contains cells derived from all three embryonic germ layers. Teratoma formation indicates that the stem cells have the capacity to give rise to all cell types in the body.

The pluripotency of ES cells can complicate their clinical application. While undifferentiated ES cells may possibly serve as sources of specific cell populations used in myocardial repair, it is essential that tight quality control be maintained with respect to the differentiated cells. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.4 However, purification methodologies continue to improve; one recent report describes a method to identify and select cardiomyocytes during human ES cell differentiation that may make these cells a viable option in the future.26

This concern illustrates the scientific challenges that accompany the use of all human stem cells, whether derived from embryonic or adult tissues. Predictable control of cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. Furthermore, long-term cell stability must be well understood before human ES-derived cells can be used in regenerative medicine. The propensity for genetic mutation in the human ES cells must be determined, and the survival of differentiated, ES-derived cells following transplantation must be assessed. Furthermore, once cells have been transplanted, undesirable interactions between the host tissue and the injected cells must be minimized. Cells or tissues derived from ES cells that are currently available for use in humans are not tissue-matched to patients and thus would require immunosuppression to limit immune rejection.18

While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation.27 However, SM-derived cardiomyocytes do not function in complete concert with native myocardium. The expression of two key proteins involved in electromechanical cell integration, N-cadherin and connexin 43, are downregulated in vivo,28 and the engrafted cells develop a contractile activity phenotype that appears to be unaffected by neighboring cardiomyocytes.29

To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Most of these procedures were carried out during open-heart surgery, although a couple of studies have investigated direct myocardial injection and transcoronary administration. Sustained ventricular tachycardia, a life-threatening arrhythmia and unexpected side-effect, occurred in early implantation studies, possibly resulting from the lack of electrical coupling between SM-derived cardiomyocytes and native tissue.30,31 Changes in preimplantation protocols have minimized the occurrence of arrhythmias in conjunction with the use of SM cells, and Phase II studies of skeletal myoblast therapy are presently underway.

In 2001, Jackson, et.al. demonstrated that cardiomyocytes and endothelial cells could be regenerated in a mouse heart attack model through the introduction of adult mouse bone marrow-derived stem cells.9 That same year, Orlic and colleagues showed that direct injection of mouse bone marrow-derived cells into the damaged ventricular wall following an induced heart attack led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells.11 Nine days after transplanting the stem cells, the newly-formed myocardium occupied nearly 70 percent of the damaged portion of the ventricle, and survival rates were greater in mice that received these cells than in those that did not. While several subsequent studies have questioned whether these cells actually differentiate into cardiomyocytes,32,33 the evidence to support their ability to prevent remodeling has been demonstrated in many laboratories.7

Based on these findings, researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells (which differentiate into all of the cellular components of blood), endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its' unique cell-surface receptors. In the past three years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.7

The results from clinical studies of BMMNC transplantation have been promising but mixed. However, it should be noted that these studies have been conducted under a variety of conditions, thereby hampering direct comparison. The cells have been delivered via open-heart surgery and endomyocardial and intracoronary catheterization. Several studies, including the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) and the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trials, have shown that intracoronary infusion of BMMNCs following a heart attack significantly improves the left ventricular (LV) ejection fraction, or the volume of blood pumped out of the left ventricle with each heartbeat.3436 However, other studies have indicated either no improvement in LV ejection fraction upon treatment37 or an increased LV ejection fraction in the control group.38 An early study that used endomyocardial injection to enhance targeted delivery indicated a significant improvement in overall LV function.39 Discrepancies such as these may reflect differences in cell preparation protocols or baseline patient statistics. As larger trials are developed, these issues can be explored more systematically.

Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. They remain multipotent following expansion in vitro, exhibit relatively low immunogenicity, and can be frozen easily. While these properties make the cells amenable to preparation and delivery protocols, scientists can also culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. This property enables their application to cardiac regeneration. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor40 and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine.41 More important, however, is the observation that MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models.4245 Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types.43

Several animal model studies have shown that treatment with MSCs significantly increases myocardial function and capillary formation.5,41 One advantage of using these cells in human studies is their low immunogenicity; allogeneic MSCs injected into infarcted myocardium in a pig model regenerated myocardium and reduced infarct size without evidence of rejection.46 A randomized clinical trial implanting MSCs after MI has demonstrated significant improvement in global and regional LV function,47 and clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.

Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement.7 These cells have been isolated and characterized in mouse, rat, and human tissues.48,49 The cells can be harvested in limited quantity from human endomyocardial biopsy specimens50 and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function.49 Separation and expansion ex vivo over a period of weeks are necessary to obtain sufficient quantities of these cells for experimental purposes. However, their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.

The endothelium is a layer of specialized cells that lines the interior surface of all blood vessels (including the heart). This layer provides an interface between circulating blood and the vessel wall. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia.4 EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells.19,5153 EPCs home in on ischemic areas, where they differentiate into new blood vessels; following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours.12 The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function.13 However, no change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.

Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts (cells that synthesize the extracellular matrix of connective tissues), and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans.

Umbilical cord blood contains enriched populations of hematopoietic stem cells and mesencyhmal precursor cells relative to the quantities present in adult blood or bone marrow.54,55 When injected intravenously into the tail vein in a mouse model of MI, human mononuclear UCB cells formed new blood vessels in the infarcted heart.56 A human DNA assay was used to determine the migration pattern of the cells after injection; although they homed only to injured areas within the heart, they were also detected in the marrow, spleen, and liver. When injected directly into the infarcted area in a rat model of MI, human mononuclear UCB cells improved ventricular function.57 Staining for CD34 and other markers found on the cell surface of hematopoietic stem cells indicated that some of the cells survived in the myocardium. Results similar to these have been observed following the injection of human unrestricted somatic stem cells from UCB into a pig MI model.58

Adult peripheral blood CD34+ cells offer the advantage of being obtained relatively easily from autologous sources.59 Although some studies using a mouse model of MI claim that these cells can transdifferentiate into cardiomyocytes, endothelial cells, and smooth muscle cells at the site of tissue injury,60 this conclusion is highly contested. Recent studies that involve the direct injection of blood-borne or bone marrow-derived hematopoietic stem cells into the infarcted region of a mouse model of MI found no evidence of myocardial regeneration following injection of either cell type.33 Instead, these hematopoietic stem cells followed traditional differentiation patterns into blood cells within the microenvironment of the injured heart. Whether these cells will ultimately find application in myocardial regeneration remains to be determined.

Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.4 The cells may be manipulated to express muscle-specific transcription factors that promote their differentiation into myotubes such as those derived from skeletal myoblasts.61 One month after these cells were implanted into the post-infarction scar in a rat model of MI, they occupied a large portion of the scar but were not functionally integrated.61 Although the effects on ventricular function were not evaluated in this study, authors noted that modified autologous fibroblasts may ultimately prove useful in elderly patients who have a limited population of autologous skeletal myoblasts or bone marrow stem cells.

As these examples indicate, many types of stem cells have been applied to regenerate damaged myocardium. In select applications, stem cells have demonstrated sufficient promise to warrant further exploration in large-scale, controlled clinical trials. However, the current breadth of application of these cells has made it difficult to compare and contextualize the results generated by the various trials. Most studies published to date have enrolled fewer than 25 patients, and the studies vary in terms of cell types and preparations used, methods of delivery, patient populations, and trial outcomes. However, the mixed results that have been observed in these studies do not necessarily argue against using stem cells for cardiac repair. Rather, preliminary results illuminate the many gaps in understanding of the mechanisms by which these cells regenerate myocardial tissue and argue for improved characterization of cell preparations and delivery methods to support clinical applications.

Future clinical trials that use stem cells for myocardial repair must address two concerns that accompany the delivery of these cells: 1) safety and 2) tracking the cells to their ultimate destination(s). Although stem cells appear to be relatively safe in the majority of recipients to date, an increased frequency of non-sustained ventricular tachycardia, an arrhythmia, has been reported in conjunction with the use of skeletal myoblasts.30,6264 While this proarrhythmic effect occurs relatively early after cell delivery and does not appear to be permanent, its presence highlights the need for careful safety monitoring when these cells are used. Additionally, animal models have demonstrated that stem cells rapidly diffuse from the heart to other organs (e.g., lungs, kidneys, liver, spleen) within a few hours of transplantation,65,66 an effect observed regardless of whether the cells are injected locally into the myocardium. This migration may or may not cause side-effects in patients; however, it remains a concern related to the delivery of stem cells in humans. (Note: Techniques to label stem cells for tracking purposes and to assess their safety are discussed in more detail in other articles in this publication).

In addition to safety and tracking, several logistical issues must also be addressed before stem cells can be used routinely in the clinic. While cell tracking methodologies allow researchers to determine migration patterns, the stem cells must target their desired destination(s) and be retained there for a sufficient amount of time to achieve benefit. To facilitate targeting and enable clinical use, stem cells must be delivered easily and efficiently to their sites of application. Finally, the ease by which the cells can be obtained and the cost of cell preparation will also influence their transition to the clinic.

The evidence to date suggests that stem cells hold promise as a therapy to regenerate damaged myocardium. Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As the results of large-scale clinical trials become available, researchers will begin to identify ways to standardize and optimize the use of these cells, thereby providing clinicians with powerful tools to mend a broken heart.

Chapter 5|Table of Contents|Chapter 7

See the article here:
Mending a Broken Heart: Stem Cells and Cardiac Repair ...

Story highlights

In other words, the impact certain variants could have on your health remains a guessing game.

"Patients often ask us what do these variants of uncertain significance mean. But in reality, we don't know most of the time ourselves. So we end up having to follow the patients for the next five, 10, 20, or 30 years to see if the patient manifests the disease or not," Wu said.

"Here, we now have a way to shorten that time because we can generate patients' induced pluripotent stem cells from blood."

How do those stem cells then help predict if a variant is harmful or not? They can be differentiated into heart cells.

If the heart cells look abnormal, that probably means the variant of uncertain significance is pathogenic, meaning it's capable of causing disease.

If the heart cells look normal, that probably means the variant of uncertain significance is actually benign.

"This is one of the very first proof of principles to show that concept," Wu said.

'An important step towards precision medicine'

The researchers found 592 genetic variants across the 54 people. While 78% of the variants were categorized as benign, there were 17 people who each carried a variant categorized as "likely pathogenic." For four of those people, their variant was hypertrophic cardiomyopathy-related.

So the researchers then took that knowledge and used CRISPR to turn the patient's stem cells with this MYL3 genetic variant from being heterozygous, meaning they have one normal and one recessive form of the variant, to being homozygous, so that they have two recessive forms of the variant.

Specifically, the researchers took the one study participant's blood cells, turned them into induced pluripotent stem cells, and then used CRISPR to edit those cells in a petri dish. The researchers then differentiated the edited stem cells so they would become heart muscle cells, and performed a comprehensive analysis to evaluate the variant, determining exactly how harmful the variant was or whether it was benign.

In this case, the study participant's variant was predicted to be benign.

A risk with using CRISPR is that it could introduce some unintended changes, but no off-target mutations were detected in the gene-edited cells, the researchers reported in their study.

"Much work remains to further develop stepping stones between editing cells in a dish and genome editing therapeutics that can treat patients, but studies such as this one help identify variants that are promising targets for therapeutic editing," said David Liu, core institute member of the Broad Institute and professor of chemistry and chemical biology at Harvard University, who was not involved in the study.

This gene-editing approach was found to be feasible in this one patient, but more research is needed to determine whether similar results would emerge among more patients.

"While it's very elegant, the major limitation of this work is that it took years of expensive work by a team of very talented scientists to do this for just one patient," said Dr. Kiran Musunuru, an associate professor of cardiovascular medicine at the University of Pennsylvania's Perelman School of Medicine, who was not involved in the new study but has conducted separate research involving CRISPR.

"It's an important step towards precision medicine, but going forward we will need to scale this up and be able to do this for dozens, hundreds, or even thousands of patients at a time, in a matter of weeks and much more cheaply," he said.

Time and cost are also limitations of this approach, Wu said.

"Cost-wise, it takes us probably about $10,000 and time-wise about six months," he said. Those six months would involve making the induced pluripotent stem cells, using CRISPR to edit the cells and then analyzing the differentiated heart cells.

Wu added, "but keep in mind that six months is actually still much better than the current alternative that we have, which is to tell patients that we don't know what the variant means."

The alternative would be following a patient with a variant for years, with the worrisome chance of a disease possibly developing or not developing. In either scenario, the patient as well as family members could have anxiety and stress.

Is this the future of gene editing?

"This addresses a major unmet need in patient care by helping determine whether your specific mutation is something to worry about," said Lagor, who was not involved in the study but has conducted separate research on CRISPR.

Then once a mutation has been identified as disease-causing, "this is an ideal platform for testing potential new drugs or gene therapy approaches in a patient-specific manner. This is truly personalized medicine," he said.

"The first therapeutic application of this technology would be to correct rare genetic diseases of the heart itself, where the potential benefit far outweighs the risk to the patient. Some of this technology already exists today, and it is now a matter of demonstrating that this can be done safely and effectively," he said.

"However, present-day forms of CRISPR technology do not work well enough in the actual heart muscle in a living being to correct a mutation for a disease like cardiomyopathy," he said. "It's possible that some future generation of gene-editing technology might be able to do the job of treating disease in the heart muscle, years or more likely decades in the future."

See original here:
Scientists edit heart muscle gene in stem cells, may be ...

Consistency

Quality Control and Testing

Product Selection & Support

HiPSC Custom Services

Human Induced Pluripotent Stem Cells (HiPSC)Top:HiPSC express pluriotency markers OCT4, Nanog, LIN28 and SSEA-4.Bottom:HiPSC differentiate into cell derivatives from the 3 embryonic layers: Neuronal marker beta III tubulin (TUJ1), Smooth Muscle Actin (SMA) and Hepatocyte Nuclear Factor 3 Beta (HNF3b).

Cutting-edge development and manufacturing provides high quality, thoroughly-characterized HiPSC cells to researchers around the world. HiPSC are generated from somatic cells, eliminating ethical considerations associated with scientific work based on embryonic stem cells. Furthermore, being donor/patient-specific, they open possibilities for a wide variety of studies in biomedical research. Donor somatic cells carry the genetic makeup of the diseased patient, hence HiPSC can be used directly to model disease on a dish.

Thus, one of the main uses of HiPSC has been in genetic disease modeling in organs and tissues, such as the brain (Alzheimers, Autism Spectrum Disorders), heart (Familial Hypertrophic, Dilated, and Arrhythmogenic Right Ventricular Cardiomyopathies), and skeletal muscle (Amyotrophic Lateral Sclerosis, Spinal Muscle Atrophy). The combination of HiPSC technology and gene editing strategies such as the CRISPR/Cas9 system creates a powerful platform in which disease-causing mutations can be created on demand and sets of isogenic cell lines (with and without mutations) serve as convenient tools for disease modeling studies.

Other applications of HiPSC and iPSC-differentiated cells include drug screening, development, efficacy and toxicity assessment. As an example, through the FDA-backed CiPA (Comprehensive in vitro Pro-Arrhythmia Assessment) initiative, HiPSC-derived cardiac muscle cells (cardiomyocytes) are poised to constitute a new standard model for the evaluation of cardiotoxicity of new drugs, which is the main reason of drug withdrawal from the market. Finally, HiPSC-differentiated cells are being used in early stage technology development for applications in regenerative medicine. Bio-printing and tissue constructs have also been considered as attractive applications for HiPSC.

Human iPSC and Derived Cells are forResearch Use Only (RUO). Not for human clinical or therapeutic use.

Read this article:
iPSC | Induced Pluripotent Stem Cells | Human | HiPSC ...