Archive for the ‘Cardiac Stem Cells’ Category

6 hours ago A cross section through a histotripsy lesion created in bovine liver tissue with the liquified cellular contents washed out revealing the remaining extracellular matrix. The scale bar represents 5mm. Credit: T.Khoklova/UW

Researchers at the University of Washington have developed a way to use sound to create cellular scaffolding for tissue engineering, a unique approach that could help overcome one of regenerative medicine's significant obstacles. The researchers will present their technique at the 168th meeting of the Acoustical Society of America (ASA), held October 27-31, 2014, at the Indianapolis Marriott Downtown Hotel.

The development of the new technique started with somewhat of a serendipitous discovery. The University of Washington team had been studying boiling histotripsy - a technique that uses millisecond-long bursts of high-intensity ultrasound waves to break apart tissue - as a method to eliminate cancerous tumors by liquefying them with ultrasound waves. After the sound waves destroy the tumors, the body should eliminate them as cellular waste. When the researchers examined these 'decellularized' tissues, however, they were surprised by what the boiling left intact.

"In some of our experiments, we discovered that some of the stromal tissue and vasculature was being left behind," said Yak-Nam Wang, a senior engineer at the University of Washington's Applied Physics Laboratory. "So we had the idea about using this to decellularize tissues for tissue engineering and regenerative medicine."

The structure that remains after decellularizing tissues is known as the extracellular matrix, a fibrous network that provides a scaffold for cells to grow upon. Most other methods for decellularizing tissues and organs involve chemical and enzymatic treatments that can cause damage to the tissues and fibers and takes multiple days. Histrostipsy, on the other hand, offers the possibility of fast decellularization of tissue with minimal damage to the matrix.

"In tissue engineering, one of the holy grails is to develop biomimetic structures so that you can replace tissues with native tissue," Wang said. Stripping away cells from already developed tissue could provide a good candidate for these structures, since the extracellular matrix already acts as the cellular framework for tissue systems, Wang said.

Due to its bare composition, the matrix also induces only a relatively weak immune response from the host. The matrix could then theoretically be fed with stem cells or cells from the same person to effectively re-grow an organ.

"The other thought is that maybe you could just implant the extracellular matrix and then the body itself would self-seed the tissues, if it's just a small patch of tissue that you're replacing," Wang said. "You won't have any immune issues, and because you have this biomimetic scaffold that's closer to the native tissue, healing would be better, and the body would recognize it as normal tissue."

Wang is currently investigating decellularization of kidney and liver tissue from large animals. Future work involves increasing the size of the decellularized tissues and assessing their in-vivo regenerative efficacy.

Explore further: The future of regenerative medicine

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High-intensity sound waves may aid regenerative medicine

13 hours ago Fruit fly larva are used to study stem cells key features. Credit: Wikipedia

The study, performed with fruit flies, describes a gene that determines whether a specialized cell conserves the capacity to become a stem cell again. Unveiling the genetic traits that favour the retention of stem cell properties is crucial for regenerative medicine. Published in Cell Reports, the article is the fruit of collaboration between researchers at IRB Barcelona and CSIC.

One kind of stem cell, those referred to as 'facultative', form parttogether with other cellsof tissues and organs. There is apparently nothing that differentiates these cells from the others. However, they have a very special characteristic, namely they retain the capacity to become stem cells again. This phenomenon is something that happens in the liver, an organ that hosts cells that stimulate tissue growth, thus allowing the regeneration of the organ in the case of a transplant. Knowledge of the underlying mechanism that allows these cells to retain this capacity is a key issue in regenerative medicine.

Headed by Jordi Casanova, research professor at the Instituto de Biologa Molecular de Barcelona (IBMB) of the CSIC and at IRB Barcelona, and by Xavier Franch-Marro, CSIC tenured scientist at the Instituto de Biologa Evolutiva (CSIC-UPF), a study published in the journal Cell Reports reveals a mechanism that could explain this capacity. Working with larval tracheal cells of Drosophila melanogaster, these authors report that the key feature of these cells is that they have not entered the endocycle, a modified cell cycle through which a cell reproduces its genome several times without dividing.

"The function of endocycle in living organisms is not fully understood," comments Xavier Franch-Marro. "One of the theories is that endoreplication contributes to enlarge the cell and confers the production of high amounts of protein". This is the case of almost all larval cells of Drosophila.

The scientists have observed that the cells that enter the endocycle lose the capacity to reactivate as stem cells. "The endocycle is linked to an irreversible change of gene expression in the cell," explains Jordi Casanova, "We have seen that inhibition of endocycle entry confers the cells the capacity to reactivate as stem cells".

Cell entry into the endocycle is associated with the expression of the Fzr gene. The researchers have found that inhibition of this gene prevents this entry, which in turn leads to the conversion of the cell into an adult progenitor that retains the capacity to reactivate as a stem cell. Therefore, this gene acts as a switch that determines whether a cell will enter mitosis (the normal division of a cell) or the endocycle, the latter triggering a totally different genetic program with a distinct outcome regarding the capacity of a cell to reactivate as a stem cell.

Explore further: Autophagy helps fast track stem cell activation

More information: Specification of Differentiated Adult Progenitors via Inhibition of Endocycle Entry in the Drosophila Trachea, Nareg J.-V. Djabrayan, Josefa Cruz, Cristina de Miguel, Xavier Franch-Marro, Jordi Casanova, Cell Reports (2014) DOI: dx.doi.org/10.1016/j.celrep.2014.09.043

In spite of considerable research efforts around the world, we still do not know the determining factors that confer stem cells their main particular features: capacity to self-renew and to divide and proliferate. The scientist ...

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A mechanism that allows a differentiated cell to reactivate as a stem cell revealed

Glossary

Below is a glossary of terms related to stem cell research and clinical trials at the Stem Cell Center. For questions about any of these terms, please call the center at 832-355-9405.

Acute myocardial infarction (AMI)The medical term for a "heart attack."Acute myocardial infarction results from a blockage in one or more of the blood vessels leading to the heart. Damage to the heart muscle results, due to the lack of blood flow.

Adult stem cellAn undifferentiated cell found among differentiated cells in a tissue or organ.Thestemcellcan renew itself and change to yield all the specialized cell types of the tissue or organ.

AkinesiaA lack of myocardial wall motion.

AllogeneicA graft or tissue from someone other than the patient such as a donor or other third-party source.

Angina or angina pectorisChest pain that occurs when diseased blood vessels restrict blood flow to the heart.

AngiogenesisA new blood vessel growth.

AngiographyAn x-raytechniqueinwhichdye is injected into the chambers of your heart or the arteries that lead to your heart (the coronary arteries). The test lets doctors measure the blood flow and blood pressure in the heart chambers and see if the coronary arteries are blocked.

AngioplastyA nonsurgical technique for treating diseased arteries by temporarily inflating a tiny balloon inside an artery.

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Stem Cell Education Center - Texas Heart Institute at St ...

A common protein plays a different role than previously thought in the opening and closing of channels that let ions flow in and out of our cells, researchers at Johns Hopkins report. Those channels are critical to life, as having the right concentrations of sodium and calcium ions in cells enables healthy brain communication, heart contraction and many other processes. The new study reveals that a form of calmodulin long thought to be dormant actually opens these channels wide. The finding is likely to bring new insight into disorders caused by faulty control of these channels, such as cardiac arrhythmias, epilepsy and Parkinson's disease, the researchers say.

A report on the finding appears in the Oct. 23 issue of the journal Cell.

In the current model, explains David Yue, M.D., Ph.D. , a professor of biomedical engineering and neuroscience at the Johns Hopkins University School of Medicine, calmodulin can do little until it binds to calcium, which changes its shape and snaps it into action. The activated calmodulin can then bind to a specialized control lever inside calcium and sodium channels, which closes the channels.

The new study revises this viewpoint by devising ways to deliver surges of calcium-free calmodulin to channels. In so doing, "it can be seen that calcium-free calmodulin is in no way dormant, but instead markedly boosts the opening of calcium and sodium channels to begin with," Yue says. When calcium binds to the "resident" calcium-free calmodulin on channels, this initial enhancement dissipates. "The two forms of calmodulin are both powerful, each imposing opposing actions that together maintain exquisite control, akin to the 'yin-yang' balance in Chinese philosophy," Yue says. "This insight into how the calmodulin-controlled lever works could ultimately help in finding treatments for a plethora of conditions that stem from faulty ion channels."

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The above story is based on materials provided by Johns Hopkins Medicine. Note: Materials may be edited for content and length.

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New view on how cells control what comes in and out

Oct 27, 2014 The dynamic interplay of calcium-free calmodulin (white yang domain) and calcium-bound calmodulin (dark yin domain) controls the opening of ion channels, shown in the background. Credit: Manu Ben-Johny and David Yue/Johns Hopkins Medicine

A common protein plays a different role than previously thought in the opening and closing of channels that let ions flow in and out of our cells, researchers at Johns Hopkins report. Those channels are critical to life, as having the right concentrations of sodium and calcium ions in cells enables healthy brain communication, heart contraction and many other processes. The new study reveals that a form of calmodulin long thought to be dormant actually opens these channels wide. The finding is likely to bring new insight into disorders caused by faulty control of these channels, such as cardiac arrhythmias, epilepsy and Parkinson's disease, the researchers say.

A report on the finding appears in the Oct. 23 issue of the journal Cell.

In the current model, explains David Yue, M.D., Ph.D. , a professor of biomedical engineering and neuroscience at the Johns Hopkins University School of Medicine, calmodulin can do little until it binds to calcium, which changes its shape and snaps it into action. The activated calmodulin can then bind to a specialized control lever inside calcium and sodium channels, which closes the channels.

The new study revises this viewpoint by devising ways to deliver surges of calcium-free calmodulin to channels. In so doing, "it can be seen that calcium-free calmodulin is in no way dormant, but instead markedly boosts the opening of calcium and sodium channels to begin with," Yue says. When calcium binds to the "resident" calcium-free calmodulin on channels, this initial enhancement dissipates. "The two forms of calmodulin are both powerful, each imposing opposing actions that together maintain exquisite control, akin to the 'yin-yang' balance in Chinese philosophy," Yue says. "This insight into how the calmodulin-controlled lever works could ultimately help in finding treatments for a plethora of conditions that stem from faulty ion channels."

Explore further: Cellular gates for sodium and calcium controlled by common element of ancient origin

More information: Cell, http://www.cell.com/cell/abstract/S0092-8674(14)01235-5

Researchers at Johns Hopkins have spotted a strong family trait in two distant relatives: The channels that permit entry of sodium and calcium ions into cells turn out to share similar means for regulating ...

Scientists at Johns Hopkins report they have figured out a key step in how "free" calciumthe kind not contained in bonesis managed in the body, a finding that could aid in the development of new treatments for a variety ...

Cells rely on calcium as a universal means of communication. For example, a sudden rush of calcium can trigger nerve cells to convey thoughts in the brain or cause a heart cell to beat. A longstanding mystery has been how ...

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Study gives new view on how cells control what comes in and out

KYOTO A team of Japanese researchers has successfully created cardiac tissue sheets generated from human induced pluripotent stem cells, according to a study in the online British journal Scientific Reports.

The team said it is the first time iPS cells have produced an integrated cardiac tissue sheet that includes vascular cells as well as cardiac muscle cells and is close to real tissue in structure.

The stem cell team, led by Kyoto University professor Jun Yamashita, hopes the achievement will contribute to the development of new treatments for heart disease, because it has already found evidence that transplanting the sheets into mice with failing hearts improves in their cardiac condition.

The team used a protein called VEGF, which is related to the growth of blood vessels, as a replacement for the Dkk1 protein previously used to create cardiac muscle sheets from iPS cells.

As a result, iPS cells were simultaneously differentiated to become cardiac muscle cells, vascular mural cells, and the endothelial cells that line the interior surface of blood vessels. The cells were cultivated into a sheet about 1 cm in diameter.

Three-layer cardiac tissue sheets were then transplanted into nine mice with dead or damaged heart muscle caused by heart attacks. In four of the mice, blood vessels formed in the area where the sheets were transplanted, leading to improved cardiac function.

The weak point of iPS cells is that there is a risk of developing cancer, but the cells did not become cancerous within two months of transplantation, the team said.

About 72 percent of the cardiac tissue sheet was made of cardiac muscle cells, while 26 percent of it consisted of endothelial cells as well as vascular mural cells. But the sheet contained a small portion of cells that had not changed, leading the team to call attention to the possibility that a cancerous change might take place over the longer term.

Yamashita said in the study that he believed the new form of cardiac sheets attached well.

Oxygen and nourishment were able to reach cardiac muscle through blood because there were blood vessels, he said.

Originally posted here:
Japanese team develops cardiac tissue sheet from human iPS cells

A team of Japanese researchers has successfully created cardiac tissue sheets generated from human induced pluripotent stem cells, according to a study published in the online British journal Scientific Reports.

The team said it is the first time iPS cells have produced an integrated cardiac tissue sheet that includes vascular cells as well as cardiac muscle cells and is close to real tissue in structure.

The stem cell researchers, led by Kyoto University professor Jun Yamashita, hopes its achievement may contribute to treatments for heart disease, as it has already found evidence that transplanting the sheets into mice with failing hearts improves in their cardiac condition.

The team used a protein called VEGF, which is related to the growth of blood vessels, as a replacement for the Dkk1 protein previously used to create cardiac muscle sheets from iPS cells.

As a result, iPS cells were simultaneously differentiated to become cardiac muscle cells, vascular mural cells, and the endothelial cells which line the interior surface of blood vessels. The cells were cultivated into a sheet about 1 cm in diameter.

Three-layer cardiac tissue sheets were then transplanted into nine mice with dead or damaged heart muscle due to cardiac infarction. In four of the mice, blood vessels formed in the area where the sheets were transplanted, leading to improved cardiac functioning.

The weak point of iPS cells is that there is a risk of developing cancer, but the cells did not become cancerous within two months of transplantation, the team said.

About 72 percent of the cardiac tissue sheet was made of cardiac muscle cells, while 26 percent consisted of endothelial cells and vascular mural cells. But the sheet contained a small portion of cells that had not changed, leading the team to call attention to the possibility of a cancerous change over the longer term.

Yamashita said in the study that he believed the cardiac sheets attached well.

Oxygen and nourishment were able to reach cardiac muscle through blood because there were blood vessels, he said.

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Japanese researchers create cardiac tissue sheet with vascular cells from iPS

A team of Japanese researchers has successfully created cardiac tissue sheets generated from human induced pluripotent stem cells, according to a study published in the online British journal Scientific Reports.

The team said it is the first time iPS cells have produced an integrated cardiac tissue sheet that includes vascular cells as well as cardiac muscle cells and is close to real tissue in structure.

The stem cell researchers, led by Kyoto University professor Jun Yamashita, hopes its achievement may contribute to treatments for heart disease, as it has already found evidence that transplanting the sheets into mice with failing hearts improves in their cardiac condition.

The team used a protein called VEGF, which is related to the growth of blood vessels, as a replacement for the Dkk1 protein previously used to create cardiac muscle sheets from iPS cells.

As a result, iPS cells were simultaneously differentiated to become cardiac muscle cells, vascular mural cells, and the endothelial cells which line the interior surface of blood vessels. The cells were cultivated into a sheet about 1 cm in diameter.

Three-layer cardiac tissue sheets were then transplanted into nine mice with dead or damaged heart muscle due to cardiac infarction. In four of the mice, blood vessels formed in the area where the sheets were transplanted, leading to improved cardiac functioning.

The weak point of iPS cells is that there is a risk of developing cancer, but the cells did not become cancerous within two months of transplantation, the team said.

About 72 percent of the cardiac tissue sheet was made of cardiac muscle cells, while 26 percent consisted of endothelial cells and vascular mural cells. But the sheet contained a small portion of cells that had not changed, leading the team to call attention to the possibility of a cancerous change over the longer term.

Yamashita said in the study that he believed the cardiac sheets attached well.

Oxygen and nourishment were able to reach cardiac muscle through blood because there were blood vessels, he said.

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Volume 9, Issue 1 Summary

A groundbreaking study on repairing damaged heart tissue through stem cell therapy has given patients hope that they may again live active lives. An international team of Mayo Clinic researchers and collaborators has done it by discovering a way to regenerate heart tissue.

Clinical trial participant Miroslav Dlacic near his home in Belgrade.

Andre Terzic, M.D., Ph.D., is the Michael S. and Mary Sue Shannon Family Director, Center for Regenerative Medicine, and the Marriott Family Professor of Cardiovascular Diseases Research at Mayo Clinic in Minnesota.

Miroslav Dlacic's heart attack changed his life drastically and seemingly forever. His damaged heart made him too tired to work in his garden or to spend much time at his leather-accessories workshop in Belgrade, Serbia. Like many patients with heart problems, Dlacic, who is 71, thought he would live his remaining years in a weakened condition.

Then, a groundbreaking Mayo Clinic trial of stem cell therapy to repair damaged heart tissue changed his life again this time for the better.

Dlacic agreed to participate in the Mayo Clinic stem cell trial through the hospital in Serbia where he is treated. Two years later, Dlacic is able to walk again without becoming worn out.

"I am more active, more peppy," he says. "I feel quite well."

"It's a paradigm shift," says Andre Terzic, M.D., Ph.D., director of Mayo Clinic's Center for Regenerative Medicine and senior investigator of the stem cell trial. "We are moving from traditional medicine, which addresses the symptoms of disease, to being legitimately able to cure disease."

For decades, treating patients with cardiac disease has typically involved managing heart damage with medication. It's a bit like driving a car without fixing a sluggish engine you manage the consequences as best you can and learn to live with them.

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Regenerating heart tissue through stem cell therapy ...

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Newswise Four scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have received a National Institutes of Health (NIH) Director's New Innovator Award that will forward revolutionary stem cell and neuro-science in medicine. The four UCLA researchers were among only 50 scientists nationwide to receive the New Innovator Award, the most of any institution represented.

Each recipient received a $2.3M award for their respective projects. These included Dr. Reza Ardehali, assistant professor of cardiology, for his research investigating novel ways to use stem cells to regenerate heart tissue; Dr. Elissa Hallem, assistant professor of microbiology, immunology and molecular genetics, for her work studying interactions between animal parasites and their hosts to foster the further understanding of human parasitic diseases; Dr. Sririam Kosuri, assistant professor of chemistry and biochemistry, for his project developing new biological system technologies to solve outstanding problems in gene regulation; and Dr. Lili Yang, assistant professor of microbiology, immunology and molecular genetics, for her work developing a new method to track special immune cells for use in new cellular therapies.

"These New Innovator Award grants are an important acknowledgement of our cutting-edge research and will help our faculty drive the revolutionary advances we are seeing in stem cell and neuro-science," said Dr. Owen Witte, professor and director of the Broad Stem Cell Research Center. "Every cellular therapy that reaches patients must begin in the laboratory with novel ideas and experiments that will lead us in new directions in medicine and ultimately improve human life. That makes these awards invaluable to our research effort."

The NIH Director'sNew Innovator Award is designed specifically to support unusually creative investigators with highly innovative research ideas at an early stage of their career. The award seeks to support exceptionally creative new scientists whose research complements ongoing efforts by NIH.

Dr. Reza Ardehali: Unlocking the Secrets to Regenerating Heart Tissue

Dr. Ardehali's cutting-edge work focuses on both human embryonic stem cells and induced pluripotent stem cells, known as human pluripotent stem cells (hPSC), to provide insights into the mechanisms involved in the differentiation and specification of heart cells. hPSC have the unique ability to become any cell type in the body. His lab recently identified several novel surface markers that can highly enrich early cardiovascular progenitor cells. When delivered into functioning human hearts that are transplanted in laboratory conditions, the progenitor cells integrate structurally and functionally into the host myocardium. These studies established the basis for future hPSC-based cardiac therapy.

Dr. Ardehali and his colleagues were also the first to directly measure limited division in the cells that make up heart muscle (cardiomyocytes), proving that cardiomyocytes divide and that such cell division is rare. This discovery resolves an important controversy over whether the heart muscle has the power to regenerate and is critical for future research that may lead to regenerating heart tissue to repair damage caused by disease or heart attack.

His 2013, California Institute for Regenerative Medicine (CIRM), the state's stem cell research agency, New Faculty Physician Scientist Translational Research Award allowed Dr. Ardehali to initiate the preclinical studies on stem cell based therapies for heart disease that were pivotal for his success in the 2014 New Innovator Award competition. The NIH grant affirms the critical success of the project-to-date, and emphasizes the creativity of Dr. Ardehali's research and its potential to have a significant impact on the creation of novel regenerative approaches to treat heart disease.

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Four UCLA Scientists Receive Prestigious Innovator Award for Pioneering Research Using Stem Cells

Stem Cell Therapy: Helping the Body Heal Itself

Stem cells are natures own transformers. When the body is injured, stem cells travel the scene of the accident. Some come from the bone marrow, a modest number of others, from the heart itself. Additionally, theyre not all the same. There, they may help heal damaged tissue. They do this by secreting local hormones to rescue damaged heart cells and occasionally turning into heart muscle cells themselves. Stem cells do a fairly good job. But they could do better for some reason, the heart stops signaling for heart cells after only a week or so after the damage has occurred, leaving the repair job mostly undone. The partially repaired tissue becomes a burden to the heart, forcing it to work harder and less efficiently, leading to heart failure.

Initial research used a patients own stem cells, derived from the bone marrow, mainly because they were readily available and had worked in animal studies. Careful study revealed only a very modest benefit, so researchers have moved on to evaluate more promising approaches, including:

No matter what you may read, stem cell therapy for damaged hearts has yet to be proven fully safe and beneficial. It is important to know that many patients are not receiving the most current and optimal therapies available for their heart failure. If you have heart failure, and wondering about treatment options, an evaluation or a second opinion at a Center of Excellence can be worthwhile.

Randomized clinical trials evaluating these different approaches typically allow enrollment of only a few patients from each hospital, and hence what may be available at the Cleveland Clinic varies from time to time. To inquire about current trials, please call 866-289-6911 and speak to our Resource Nurses.

Cleveland Clinic is a large referral center for advanced heart disease and heart failure we offer a wide range of therapies including medications, devices and surgery. Patients will be evaluated for the treatments that best address their condition. Whether patients meet the criteria for stem cell therapy or not, they will be offered the most advanced array of treatment options.

Allogenic: from one person to another (for example: organ transplant)

Autogenic: use of one's own tissue

Myoblasts: immature muscle cells, may be able to change into functioning heart muscle cells

Stem Cells: cells that have the ability to reproduce, generate new cells, and send signals to promote healing

Excerpt from:
Stem-Cell Therapy and Repair after Heart Attack and Heart ...

Category: Science & Technology Posted: October 3, 2014 01:55PM Author: Guest_Jim_*

Heart attacks are pretty serious and something very hard to recover from, in part because heart cells do not multiply and there are few cardiac muscle stem cells to repair the damage. Cardiac patches have been created to replace damaged cells, but because of how they are made, these patches can cause their own health problems. Researchers at Tel Aviv University have recently developed a new hybrid patch that could address those problems.

Traditionally the patches are made by growing cardiac tissue on a collagen scaffold from pig hearts. One of the problems with this approach is the potential for antigens that will trigger an immune response, causing the patient's body to attack the patch. To get around this the researchers instead harvest fatty tissue from the patient's stomach, as the body will not attack its own cells. This left an issue with connectivity, as the cells in the patch must respond to the electrical signals of the heart, and engineered patches do not immediately form the necessary connections. The solution the researchers tried was to deposit gold nanoparticles onto the cardiac tissue, providing the needed conductivity.

So far the nonimmunogenic hybrid patch has shown itself to transfer electrical signals faster and more efficiently than scaffolds without the gold nanoparticles, when tested in animals. The next step for the technology is to test it in larger animals, and eventually perform clinical trials.

Source: American Friends of Tel Aviv University

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Gold Nanoparticles Used to Improve Cardiac Patches

Freeport, Grand Bahama (PRWEB) October 02, 2014

Dr. Todd K. Malan, M.D., presented to the Grand Bahama Medical & Dental Association 14th Annual Scientific Educational Conference on the science, safety and efficacy of adipose- (fat) derived stem and regenerative cells (ADRCs) for ischemic heart disease and other unmet healthcare needs.

"It was an honor to participate in this conference with medical leadership that values this technology and works so tirelessly to serve the people of Grand Bahama," said Dr. Todd Malan." It is an opportunity for us to work closely with local doctors to improve the quality and standards of care for all patients."

Dr. Malan explained the interrelationship between tissue ischemia, inflammation, autoimmune response and cell death and how ADRCs have combined mechanisms known to assist in repairing multi-factorial illnesses associated with those issues.

According to Malan,The procedure begins with the extraction of a persons body fat, a process done using advanced water-assisted liposuction technology. The persons own adult stem cells are then separated from the fat tissue using a European Union-approved cell processing device."

Immediately following this, the cardiologist injects these cells into and around the low blood flow regions of the heart via a cathetera protocol which allows for better targeting of the cells to repair damaged heart tissue.

Adult stem cell therapy for heart disease is emerging as a new alternative for patients with severe heart conditions who want to live a normal life but are restricted in activities they can no longer do.

"As a leader in providing cell therapy, Okyanos is very excited to bring this innovative treatment to patients in a near-shore, regulated jurisdiction with a new standard of care, said Matt Feshbach, CEO of Okyanos. We welcome the opportunity to help those patients with limited options a chance to live a normal life.

Offering this minimally invasive adult stem cell treatment in their new cardiac catherization lab, Okyanos is scheduled to open in October in Freeport, Grand Bahama.

About Okyanos Heart Institute: (Oh key AH nos)

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Okyanos Presents the Science, Safety, and Efficacy of Adult Stem Cell Therapy

Oct 01, 2014

Cancer vaccines have recently emerged as a promising approach for killing tumor cells before they spread. But so far, most clinical candidates haven't worked that well. Now, scientists have developed a new way to deliver vaccines that successfully stifled tumor growth when tested in laboratory mice. And the key, they report in the journal ACS Nano, is in the vaccine's unique stealthy nanoparticles.

Hiroshi Shiku, Naozumi Harada and colleagues explain that most cancer vaccine candidates are designed to flag down immune cells, called macrophages and dendritic cells, that signal "killer" T cells to attack tumors. The problem is that approaches based on targeting these generally circulating immune cells have not been very successful. But recent research has suggested that a subset of macrophages only found deep inside lymph nodes could play a major role in slowing cancer. But how could one get a vaccine to these special immune cells without first being gobbled up by the macrophages and dendritic cells circulating in the body? Shiku's team wanted to see if stealthy nanoparticles they had developed and clinically tested in patients might hold the answer.

The researchers injected the nanoparticles into mice. They found that the particles, which have no electric charge or surface molecules that would attract the attention of circulating immune cells, were able to enter the mice's lymph nodes. But once inside the lymph nodes' core, the special kind of macrophage engulfed the particles. When molecules for signaling killer T cells were put inside the nanoparticles, they hindered tumor growth far better than existing vaccines.

Explore further: Hitchhiking vaccines boost immunity

More information: "Nanogel-Based Immunologically Stealth Vaccine Targets Macrophages in the Medulla of Lymph Node and Induces Potent Antitumor Immunity" ACS Nano, 2014, 8 (9), pp 92099218. DOI: 10.1021/nn502975r

Abstract

Because existing therapeutic cancer vaccines provide only a limited clinical benefit, a different vaccination strategy is necessary to improve vaccine efficacy. We developed a nanoparticulate cancer vaccine by encapsulating a synthetic long peptide antigen within an immunologically inert nanoparticulate hydrogel (nanogel) of cholesteryl pullulan (CHP). After subcutaneous injection to mice, the nanogel-based vaccine was efficiently transported to the draining lymph node, and was preferentially engulfed by medullary macrophages but was not sensed by other macrophages and dendritic cells (so-called "immunologically stealth mode"). Although the function of medullary macrophages in T cell immunity has been unexplored so far, these macrophages effectively cross-primed the vaccine-specific CD8+ T cells in the presence of a Toll-like receptor (TLR) agonist as an adjuvant. The nanogel-based vaccine significantly inhibited in vivo tumor growth in the prophylactic and therapeutic settings, compared to another vaccine formulation using a conventional delivery system, incomplete Freund's adjuvant. We also revealed that lymph node macrophages were highly responsive to TLR stimulation, which may underlie the potency of the macrophage-oriented, nanogel-based vaccine. These results indicate that targeting medullary macrophages using the immunologically stealth nanoparticulate delivery system is an effective vaccine strategy.

Many vaccines, including those for influenza, polio, and measles, consist of a killed or disabled version of a virus. However, for certain diseases, this type of vaccine is ineffective, or just too risky.

Breast cancer cells can lay the groundwork for their own spread throughout the body by coaxing cells within lymphatic vessels to send out tumor-welcoming signals, according to a new report by Johns Hopkins ...

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'Stealth' nanoparticles could improve cancer vaccines

Because heart cells cannot multiply and cardiac muscles contain few stem cells, heart tissue is unable to repair itself after a heart attack. Now Tel Aviv University researchers are literally setting a new gold standard in cardiac tissue engineering.

Dr. Tal Dvir and his graduate student Michal Shevach of TAU's Department of Biotechnology, Department of Materials Science and Engineering, and Center for Nanoscience and Nanotechnology, have been developing sophisticated micro- and nanotechnological tools -- ranging in size from one millionth to one billionth of a meter -- to develop functional substitutes for damaged heart tissues. Searching for innovative methods to restore heart function, especially cardiac "patches" that could be transplanted into the body to replace damaged heart tissue, Dr. Dvir literally struck gold. He and his team discovered that gold particles are able to increase the conductivity of biomaterials.

In a study published by Nano Letters, Dr. Dvir's team presented their model for a superior hybrid cardiac patch, which incorporates biomaterial harvested from patients and gold nanoparticles. "Our goal was twofold," said Dr. Dvir. "To engineer tissue that would not trigger an immune response in the patient, and to fabricate a functional patch not beset by signalling or conductivity problems."

A scaffold for heart cells

Cardiac tissue is engineered by allowing cells, taken from the patient or other sources, to grow on a three-dimensional scaffold, similar to the collagen grid that naturally supports the cells in the heart. Over time, the cells come together to form a tissue that generates its own electrical impulses and expands and contracts spontaneously. The tissue can then be surgically implanted as a patch to replace damaged tissue and improve heart function in patients.

According to Dr. Dvir, recent efforts in the scientific world focus on the use of scaffolds from pig hearts to supply the collagen grid, called the extracellular matrix, with the goal of implanting them in human patients. However, due to residual remnants of antigens such as sugar or other molecules, the human patients' immune cells are likely to attack the animal matrix.

In order to address this immunogenic response, Dr. Dvir's group suggested a new approach. Fatty tissue from a patient's own stomach could be easily and quickly harvested, its cells efficiently removed, and the remaining matrix preserved. This scaffold does not provoke an immune response.

Using gold to create a cardiac network

The second dilemma, to establish functional network signals, was complicated by the use of the human extracellular matrix. "Engineered patches do not establish connections immediately," said Dr. Dvir. "Biomaterial harvested for a matrix tends to be insulating and thus disruptive to network signals."

At his Laboratory for Tissue Engineering and Regenerative Medicine, Dr. Dvir explored the integration of gold nanoparticles into cardiac tissue to optimize electrical signaling between cells. "To address our electrical signalling problem, we deposited gold nanoparticles on the surface of our patient-harvested matrix, 'decorating' the biomaterial with conductors," said Dr. Dvir. "The result was that the nonimmunogenic hybrid patch contracted nicely due to the nanoparticles, transferring electrical signals much faster and more efficiently than non-modified scaffolds."

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A heartbeat away? Hybrid 'patch' could replace transplants

Sep 23, 2014 by Mike Williams Three images reveal the details of heart-defect patches created at Rice University and Texas Childrens Hospital. At top, three otherwise identical patches darken with greater concentrations of carbon nanotubes, which improve electrical signaling between immature heart cells. At center, a scanning electron microscope image shows a patchs bioscaffold, with pores big enough for heart cells to invade. At bottom, a near-infrared microscopy image shows the presence of individually dispersed single-walled nanotubes. Credit: Jacot Lab/Rice University

(Phys.org) Carbon nanotubes serve as bridges that allow electrical signals to pass unhindered through new pediatric heart-defect patches invented at Rice University and Texas Children's Hospital.

A team led by bioengineer Jeffrey Jacot and chemical engineer and chemist Matteo Pasquali created the patches infused with conductive single-walled carbon nanotubes. The patches are made of a sponge-like bioscaffold that contains microscopic pores and mimics the body's extracellular matrix.

The nanotubes overcome a limitation of current patches in which pore walls hinder the transfer of electrical signals between cardiomyocytes, the heart muscle's beating cells, which take up residence in the patch and eventually replace it with new muscle.

The work appears this month in the American Chemical Society journal ACS Nano. The researchers said their invention could serve as a full-thickness patch to repair defects due to Tetralogy of Fallot, atrial and ventricular septal defects and other defects without the risk of inducing abnormal cardiac rhythms.

The original patches created by Jacot's lab consist primarily of hydrogel and chitosan, a widely used material made from the shells of shrimp and other crustaceans. The patch is attached to a polymer backbone that can hold a stitch and keep it in place to cover a hole in the heart. The pores allow natural cells to invade the patch, which degrades as the cells form networks of their own. The patch, including the backbone, degrades in weeks or months as it is replaced by natural tissue.

Researchers at Rice and elsewhere have found that once cells take their place in the patches, they have difficulty synchronizing with the rest of the beating heart because the scaffold mutes electrical signals that pass from cell to cell. That temporary loss of signal transduction results in arrhythmias.

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Nanotubes can fix that, and Jacot, who has a joint appointment at Rice and Texas Children's, took advantage of the surrounding collaborative research environment.

"This stemmed from talking with Dr. Pasquali's lab as well as interventional cardiologists in the Texas Medical Center," Jacot said. "We've been looking for a way to get better cell-to-cell communications and were concentrating on the speed of electrical conduction through the patch. We thought nanotubes could be easily integrated."

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Nanotubes help healing hearts keep the beat

Frankfurt, Germany (PRWEB) September 19, 2014

The Translational Research Institute TRI Medical announced today that its new ND Infusion Catheter is being used in a first-in-man procedure at the University of Frankfurt.

The study commenced on September 4th, 2014 at the University of Frankfurt, Department of Cardiology. The use of the new catheter demonstrated a number of advancements in the delivery of regenerative therapeutics, commonly known as stem cells. We are at the forefront of revolutionizing stem cell delivery to the heart, TRI Medicals Nabil Dib, MD, Msc, offered. The ND Infusion Catheter provides safety and potential efficacy. The catheter also reduces the procedure time to approximately 15 minutes; enabling patients to walk and resume activities in about 2 hours, Dr. Dib continued.

The renowned German Cardiology Center at the University of Frankfurt has extensive experience with the development of cardiac cell-based regenerative therapeutics. Prof. Dr. Andreas M. Zeiher, Chairman of the Department of Cardiology at the University of Frankfurt stated The catheter provides the unique potential to precisely regulate coronary blood flow, while administering cells directly into the heart thus improving safety and potentially efficacy. The innovative design of the catheter's balloon accommodates different vessel sizes, avoiding the need to use multiple catheters, reducing potential risks associated with exchanging the balloon catheter when treating different coronary arteries in an individual patient.

Prior to the first-in-man procedure, extensive cell compatibility testing of bone marrow derived cells with the ND Infusion Catheter revealed that the catheter preserved cell viability and functionality, Stefanie Dimmeler, PhD and Director of the Institute of Cardiovascular Regeneration, Centre of Molecular Medicine stated. The testing proved that the cells are compatible with the ND Infusion Catheter. We see this as potential improvements in safety and clinical outcomes related to cell function and efficacy in patients, Dr. Dimmeler offered.

Safety was top-of-mind when we initiated the first-in-man procedure in Frankfurt. We are elated to report that the procedures outcomes were successful, Dr. Dib stated. Earlier studies revealed that the ND Infusion Catheter reduces cellular clumping, preserves cell viability, improves dispersion and reduces radial forces on the vessel walls during balloon inflation; which collectively might improve patient safety and clinical outcomes.

TRI Medicals Ron Anson, Vice President of Business Development shared The catheters unique design features provide physicians with a valuable new tool in the delivery of specified fluids such as stem cells. We expect to see significant growth in the stem cell research marketplace for the new, state-of-the-art ND Infusion Catheter.

ABOUT TRI Medical TRI Medical is a privately held, medical device development company. TRI Medical is dedicated to providing a pathway to regulatory approval that is efficient, predictable and cost effective.

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Media inquiries regarding TRI Medical, its capabilities and for additional information regarding the ND Infusion Catheter contact: DeAnn Dana Phone: 480.309.2884 Email: DDana(at)TRImedical.com TRI Medical website: http://www.trimedical.com

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First-in-man procedure utilizes a new method of stem cell delivery

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Study Links Sex Hormone Levels in the Blood to Risk of Sudden Cardiac Arrest Measuring the levels of sex hormones in patients blood may identify patients likely to suffer a sudden cardiac arrest, a heart rhythm disorder that is fatal in 95 percent of patients. A new study, published online by the peer-reviewed journal Heart Rhythm, shows that lower levels of testosterone, the predominant male sex hormone, were found in men who had a sudden cardiac arrest. Higher levels of estradiol, the major female sex hormone, were strongly associated with greater chances of having a sudden cardiac arrest in both men and women. CONTACT: Sally Stewart, 310-248-6566; Email sally.stewart@cshs.org

Cedars-Sinai Shortens Premature Infants Intensive Care Stays by 21 Percent in Past Three Years The amount of time premature babies spend in Cedars-Sinais Neonatal Intensive Care Unit, part of the Maxine Dunitz Childrens Health Center, has declined dramatically during the past three years, with the average length of stay dropping from 21 days to 17 days. In recent years there have been some notable medical advances, such as personalized nutrition therapy that helps the smallest infants gain weight, nonsurgical procedures to heal heart defects and new medical protocols for mothers likely to deliver a premature infant. All have contributed to more rapidly improving the health of premature infants and shortening the infants hospital stays. But one of the main reasons for the shorter hospitalizations is a renewed emphasis on coordinating each babys various and complex health needs. CONTACT: Soshea Leibler, 213-215-8000; Email soshea.leibler@cshs.org

Combining Antibodies, Iron Nanoparticles and Magnets Steers Stem Cells to Injured Organs Researchers at the Cedars-Sinai Heart Institute infused antibody-studded iron nanoparticles into the bloodstream to treat heart attack damage. The combined nanoparticle enabled precise localization of the bodys own stem cells to the injured heart muscle. The study, which focused on laboratory rats, was published in the online peer reviewed journal Nature Communications. The study addresses a central challenge in stem cell therapeutics: how to achieve targeted interactions between stem cells and injured cells. CONTACT: Sally Stewart, 310-248-6566; Email sally.stewart@cshs.org

Cedars-Sinai Presents Educational Program on Pituitary Disorders for Patients and Families Disorders of the pituitary gland often cause gradual onset of challenging and difficult-to-manage symptoms, and it is not uncommon for patients to consult doctor after doctor in search of an accurate diagnosis and the hope of treatment. In a one-day conference in Huntington Beach on Sept. 28, pituitary experts from Cedars-Sinai will provide an update for patients and their families on the most recent advances in the diagnosis and treatment of pituitary disorders. Patients will be able to engage in discussions and Q&A sessions with the faculty. CONTACT: Sandy Van, 808-526-1708; Email sandy@prpacific.com

Researchers Developing Noninvasive Method for Diagnosing Common, Painful Back Condition An interdisciplinary research team in the Cedars-Sinai Biomedical Imaging Research Institute, Department of Biomedical Sciences, Regenerative Medicine Institute and Department of Surgery received a grant from the National Institutes of Health (NIH) to develop the first imaging technique used to identify biomarkers that could indicate patients have a painful, degenerative back condition. Biomarkers are certain body substances, such as proteins or body fluids that can indicate specific health conditions. When noninvasive imaging procedures can identify exactly where the biomarkers are, researchers may alleviate the need for painful and invasive diagnostic procedures and, in the future, provide targeted, stem cell-based therapies to patients with the condition. CONTACT: Cara Martinez, 310-423-7798; Email cara.martinez@cshs.org

Cedars-Sinais New Comprehensive Transplant Center Opens The new home of the Cedars-Sinai Comprehensive Transplant Center opens Monday and consolidates the clinical and administrative services for liver, kidney, lung and pancreas transplant patients. The four programs were previously housed at several locations on the 24-acre medical center campus, but now transplant patients can have nearly all of their medical needs addressed at one location. The three-story facility covers 36,500 square feet and is located at 8900 Beverly Blvd., two blocks from the main medical center campus. The new center has 22 exam rooms, infusion therapy and phlebotomy services, patient education space and an outpatient procedure room. Two floors of underground parking and valet parking service are available to patients and their families. (High resolution photos available upon request) CONTACT: Laura Coverson, 310-423-5215; Email laura.coverson@cshs.org

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Cedars-Sinai Medical Tip Sheet for Sept. 2014

Kotlikoff lab

Optogenetic proteins enable visualization of a developing heart.

New technologies involving optogenetic proteins, which use light to control and observe cells with unprecedented precision, have begun to illuminate processes underlying cellular behavior and the effects of cell- and gene-based therapies. Cornell researchers are developing advanced forms of these proteins to create a toolkit to make them more widely available to scientists.

With a five-year, $3.1 million grant from the National Institutes of Healths Heart, Lung and Blood Institute, the team will develop the Cornell Heart, Lung and Blood Resource for Optogenetic Mice (CHROMus), which will incorporate optogenetic proteins in mice and human stem cells. Scientists use such tools to control and observe how different types of cells function and interact.

We will target these tools so that they can be combined to study diseases of the heart, lungs, vasculature and blood, said Dr. Michael Kotlikoff, the Austin O. Hooey Dean of Veterinary Medicine at Cornells College of Veterinary Medicine and the projects lead investigator. Researchers will be able to use them to address a broad set of health issues, including heart attack, stroke, asthma and immune diseases.

Marrying optics and genetics, optogenetics enables scientists to use light to trigger and monitor the behavior of cells engineered to contain one or both of two types of designer proteins: effectors, which respond to light by activating the cell they are on, or sensors, which fluoresce when a cell has been activated.

Effectors and sensors can be engineered into specific kinds of cells and color-coded, letting scientists noninvasively trigger one type to see how another type responds. One can see different cell types light up in living animals, giving direct insight into specific cells roles in complex biological systems.

The lines of CHROMus mice developed in this project are designed to be easily crossbred, creating a combinatorial platform that will allow scientists to customize sets of effectors and sensors including new sensors from the Kotlikoff lab into the specific cell types they want to study.

For example, our lab is particularly interested in using these tools to study the control of blood flow to tissues what happens before, during and after major events like stroke and cardiac infarction, and how abnormal rhythms develop after heart injury, said Kotlikoff. Arrhythmias following a heart attack are the single most common cause of acute death in the western world, and how they can be prevented requires a better understanding of how, why and where they arise. Optogenetic tools let us look directly at relevant cells throughout the heart to determine their role in these dangerous and often fatal events.

The tools will be designed to allow scientists to ask and answer similar questions related to vascular and lung diseases, such as the role of the immune system in asthma and stroke, and how therapeutic stem cells integrate within the tissue that they are designed to repair.

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Optogenetics shed light on cardiac, lung, immune disease

PUBLIC RELEASE DATE:

10-Sep-2014

Contact: Sally Stewart sally.stewart@cshs.org 310-248-6566 Cedars-Sinai Medical Center

LOS ANGELES Researchers at the Cedars-Sinai Heart Institute infused antibody-studded iron nanoparticles into the bloodstream to treat heart attack damage. The combined nanoparticle enabled precise localization of the body's own stem cells to the injured heart muscle.

The study, which focused on laboratory rats, was published today in the online peer reviewed journal Nature Communications. The study addresses a central challenge in stem cell therapeutics: how to achieve targeted interactions between stem cells and injured cells.

Although stem cells can be a potent weapon in the fight against certain diseases, simply infusing a patient with stem cells is no guarantee the stem cells will be able to travel to the injured area and work collaboratively with the cells already there.

"Infusing stem cells into arteries in order to regenerate injured heart muscle can be inefficient," said Eduardo Marbn, MD, PhD, director of the Cedars-Sinai Heart Institute, who led the research team. "Because the heart is continuously pumping, the stem cells can be pushed out of the heart chamber before they even get a chance to begin to heal the injury."

In an attempt to target healing stem cells to the site of the injury, researchers coated iron nanoparticles with two kinds of antibodies, proteins that recognize and bind specifically to stem cells and to injured cells in the body. After the nanoparticles were infused into the bloodstream, they successfully tracked to the injured area and initiated healing.

"The result is a kind of molecular matchmaking," Marbn said. "Through magnetic resonance imaging, we were able to see the iron-tagged cells traveling to the site of injury where the healing could begin. Furthermore, targeting was enhanced even further by placing a magnet above the injured heart."

The Cedars-Sinai Heart Institute has been at the forefront of developing investigational stem cell treatments for heart attack patients. In 2009, Marbn and his team completed the world's first procedure in which a patient's own heart tissue was used to grow specialized heart stem cells. The specialized cells were then injected back into the patient's heart in an effort to repair and regrow healthy muscle in a heart that had been injured by a heart attack. Results, published in The Lancet in 2012, showed that one year after receiving the stem cell treatment, heart attack patients demonstrated a significant reduction in the size of the scar left on the heart muscle.

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Combining antibodies, iron nanoparticles and magnets steers stem cells to injured organs

4 hours ago

What if repairing large segments of damaged muscle tissue was as simple as mobilizing the body's stem cells to the site of the injury? New research in mice and rats, conducted at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine, suggests that "in body" regeneration of muscle tissue might be possible by harnessing the body's natural healing powers.

Reporting online ahead of print in the journal Acta Biomaterialia, the research team demonstrated the ability to recruit stem cells that can form muscle tissue to a small piece of biomaterial, or scaffold that had been implanted in the animals' leg muscle. The secret to success was using proteins involved in cell communication and muscle formation to mobilize the cells.

"Working to leverage the body's own regenerative properties, we designed a muscle-specific scaffolding system that can actively participate in functional tissue regeneration," said Sang Jin Lee, Ph.D., assistant professor of regenerative medicine and senior author. "This is a proof-of-concept study that we hope can one day be applied to human patients."

The current treatment for restoring function when large segments of muscle are injured or removed during tumor surgery is to surgically move a segment of muscle from one part of the body to another. Of course, this reduces function at the donor site.

Several scientific teams are currently working to engineer replacement muscle in the lab by taking small biopsies of muscle tissue, expanding the cells in the lab, and placing them on scaffolds for later implantation. This approach requires a biopsy and the challenge of standardizing the cells.

"Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration," said Lee.

Most tissues in the body contain tissue-specific stem cells that are believed to be the "regenerative machinery" responsible for tissue maintenance. It was these cells, known as satellite or progenitor cells, that the scientists wanted to mobilize.

First, the Wake Forest Baptist scientists investigated whether muscle progenitor cells could be mobilized into an implanted scaffold, which basically serves as a "home" for the cells to grow and develop. Scaffolds were implanted in the lower leg muscle of rats and retrieved for examination after several weeks.

Lab testing revealed that the scaffolds contained muscle satellite cells as well as stem cells that could be differentiated into muscle cells in the lab. In addition, the scaffold had developed a network of blood vessels, with mature vessels forming four weeks after implantation.

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Research in rodents suggests potential for 'in body' muscle regeneration

Prof Noel Caplice, director of the Centre for Research in Vascular Biology at University College Cork, displays his stent mesh. Photograph: Michael MacSweeney/Provision

As Prof Noel Caplice describes it, a revolutionary new system that avoids putting patients through heart bypass operations was literally a back-of- the-garage effort.

A cardiologist in Cork, he came up with the treatment when working as a cardiologist at the Mayo Clinic seven years ago. During this time, Caplice and an engineer friend worked on prototype meshes and attaching these to stents.

The treatment introduces cells that encourage the body to make new blood vessels that grow past the blockage, actually reversing the disease in as little as three or four weeks.

The treatment may also offer hope for patients suffering from other cardiovascular disorders such as peripheral artery disease, a common risk in diabetes. And, because it uses the patients own cells, there is no question of rejection, says Caplice, director of University College Corks Centre for Research in Vascular Biology.

This would represent a major step forward in the treatment of coronary artery disease, he adds. Instead of open-heart surgery and stitching in arteries to bypass a blockage, it causes the body to grow its own bypass. He is leading the research, which also involves the Mayo Clinic in the US, and the team has published a paper describing the work in the current issue of the journal Biomaterials.

He came up with the idea when working as a cardiologist at the Mayo Clinic seven years ago, he says.

One area we were interested in was patients who were inoperable, patients who were too ill to face open-heart surgery and who had no options. That represents about 20 to 25 per cent of all patients with coronary artery disease.

He was a scientist physician while at the Mayo as he is now, doing research but also working with patients, and he ran his own laboratory. He originally thought of introducing stem cells to encourage blood vessel growth, but when injected they go everywhere, you cant direct them in the body.

Caplice is also a consultant cardiologist at Cork University Hospital.

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Bypassing surgery for new cardiac treatment

3 hours ago Credit: National Institutes of Health (common fund)

Researchers of the ISREC Institute at the School of Life Sciences, EPFL, have deciphered the mechanism whereby some microRNAs are retained in the cell while others are secreted and delivered to neighboring cells.

There are many ways cells can communicate with each other. One important mode is the release by a cell of signaling molecules that can bind receptors expressed on the surface of another cell to initiate a specific response. In other cases, cells release small vesicles that are packed with signaling molecules of one or more types; such vesicles can fuse with, or be uptaken by, other cells that internalize their content. Exosomes are small vesicles (also called microvesicles) produced by virtually all cell types. After their release to the extracellular environment like the interstices amongst cells, the blood or other body fluids exosomes can fuse with neighboring or distant cells, to which they transfer their cargo of functional molecules. Remarkably, exosomes not only contain conventional signaling molecules like proteins and peptides but also nucleic acids, such as RNAs and DNA fragments, which can horizontally transfer genetic information from one cell to another.

Modulators born within the cells

microRNAs are small RNA molecules that can tune cell behavior by directly modulating the stability of other RNA molecules, called messenger RNAs (mRNAs), which are the precursors of all cellular proteins. Several dozen functional microRNA species are produced by each cell type. These may target hundreds of mRNAs to finely modulate the global protein output of the cell. Recent studies have shown that microRNAs are packed, along with other molecules, into exosomes and are secreted to the extracellular environment by many distinct cell types. This discovery suggests a new mechanism of cell communication involving the ability of exosomal microRNAs to "reprogram" the gene expression of cells that have internalized them. For example, some of the internalized microRNAs could influence the cell's ability to produce certain proteins that, in turn, may affect the cell functions and behavior.

Sorting out microRNAs

Interestingly, the microRNA composition of exosomes may differ from that of the producer cell. Indeed, some microRNA species can be abundant in the cell but scarce in its exosomes, and vice versa. This finding suggests that the sorting of specific microRNAs to exosomes may be actively regulated, although the underlying mechanisms have remained elusive. With the financial support of the Fonds National Suisse de la Recherche Scientifique (SNSF), Michele De Palma and his colleagues at EPFL and at the Swiss Institute of Bioinformatics (SIB) of the University of Lausanne, have now identified a mechanism that may explain the differential incorporation of microRNAs into exosomes. By performing RNA sequencing and bioinformatic modeling of the data, the researchers found that the sorting of microRNAs to exosomes is directly controlled by the abundance of the mRNAs they target in the producer cell. When the target mRNAs of a given microRNA increase in the cell for example as a consequence of cell activation the microRNA is more likely to be retained in the cell and excluded from exosomes. Conversely, if the mRNA levels decline, the microRNA is loaded into exosomes and secreted. These findings imply that the secretion of microRNAs through exosomes is a mechanism whereby cells rapidly dispose the microRNAs that are in excess of their target mRNAs.

"It may seem a quite intuitive and straightforward mechanism," explains Mario Leonardo Squadrito, a leading author of the study, "but investigating the cross-talk between microRNAs and their targeted transcripts has proven challenging and required complex bioinformatic analyses." The authors also took advantage of lentiviral vectors they had developed to specifically introduce or delete selected microRNAs, or their targeted mRNAs, in the cells. "These experiments have been crucial to document how microRNAs can dynamically traffic from the cell cytoplasm to exosomes, in response to changes of the RNA levels," adds Squadrito.

Biological markers

The microRNAs contained in circulating exosomes ("microRNA signatures") are increasingly recognized as potential biomarkers of disease and response to therapy. The findings of De Palma and colleagues not only identify a general mechanism regulating microRNA sorting to exosomes, but may also help understand how the microRNA signatures observed in circulating exosomes originate from within the cells. For example, patients with some types of cancer display specific microRNA signatures in their blood that may reflect the altered, and possibly evolving, mRNA (and protein) expression profiles of their tumors. Another important area of research is the analysis of the fate of the microRNAs once the exosomes are internalized by cells. "Although our findings suggest that a significant proportion of the internalized microRNAs may be degraded, we employed sensitive new techniques to demonstrate that they retain the ability to modulate gene expression in the target cell," explains Caroline Baer, another leading author of the study. "A fascinating side of the story is that cells produce profuse amounts of exosomes packed with microRNAs. If cells of different type and origin can effectively exchange this form of genetic information, their boundaries must be less tight than we used to think."

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A better understanding of cell to cell communication

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue, Vanderbilt University investigators have discovered.

The findings, published recently in Cell Reports, offer insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack.

The heart has long been considered to be an organ without regenerative potential, said Antonis Hatzopoulos, Ph.D., associate professor of Medicine and Cell and Developmental Biology.

"People thought that the same heart you had as a young child, you had as an old man or woman as well," he said.

Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

Hatzopoulos and colleagues postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development.

Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries -- a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

The finding that coronary arteries house a cardiac stem cell "niche" has interesting implications, Hatzopoulos said. Coronary artery disease -- the No. 1 killer in the United States -- would impact this niche.

"Our study suggests that coronary artery disease could lead to heart failure not only by blocking the arteries and causing heart attacks, but also by affecting the way the heart is maintained and regenerated," he said.

The current research follows a previous study in which Hatzopoulos and colleagues demonstrated that after a heart attack, endothelial cells give rise to the fibroblasts that generate scar tissue.

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Coronary arteries hold heart-regenerating cells

PUBLIC RELEASE DATE:

20-Aug-2014

Contact: Craig Boerner craig.boerner@vanderbilt.edu 615-322-4747 Vanderbilt University Medical Center

Endothelial cells residing in the coronary arteries can function as cardiac stem cells to produce new heart muscle tissue, Vanderbilt University investigators have discovered.

The findings, published recently in Cell Reports, offer insights into how the heart maintains itself and could lead to new strategies for repairing the heart when it fails after a heart attack.

The heart has long been considered to be an organ without regenerative potential, said Antonis Hatzopoulos, Ph.D., associate professor of Medicine and Cell and Developmental Biology.

"People thought that the same heart you had as a young child, you had as an old man or woman as well," he said.

Recent findings, however, have demonstrated that new heart muscle cells are generated at a low rate, suggesting the presence of cardiac stem cells. The source of these cells was unknown.

Hatzopoulos and colleagues postulated that the endothelial cells that line blood vessels might have the potential to generate new heart cells. They knew that endothelial cells give rise to other cell types, including blood cells, during development.

Now, using sophisticated technologies to "track" cells in a mouse model, they have demonstrated that endothelial cells in the coronary arteries generate new cardiac muscle cells in healthy hearts. They found two populations of cardiac stem cells in the coronary arteries a quiescent population in the media layer and a proliferative population in the adventitia (outer) layer.

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Vanderbilt researchers find that coronary arteries hold heart-regenerating cells