Archive for the ‘Bone Marrow Stem Cells’ Category

SAN DIEGO, July 28 (UPI) -- A new drug aimed at dormant cancer stem cells that hide in the hypoxic zones of bone marrow, where most drugs can't reach, is currently entering 5 Phase II clinical trials after it was shown to make blood cancer treatment more effective.

Researchers in a Phase I clinical trial, the results of which are published in The Lancet Haematology, found that the drug vismodegib was effective against three types of blood cancer -- refractory or resistant myeloid leukemia, myelodysplastic syndrome and myelofibrosis.

Vismodegib inhibits the Hedgehog signaling pathway, which is essential to both vertebrate embryonic development and has been implicated in the development of some cancers. The drug, trade name Erivedge, is already approved in the U.S. and Europe for treatment of metastatic or locally advanced basal cell carcinoma.

"Our hope is that this drug will enable more effective treatment to begin earlier and that with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation," said Dr. Catriona Jamieson, chief of the Division of Regenerative Medicine in the School of Medicine at the University of California San Diego, in a press release. "It's all about reducing the burden of disease by intervening early."

Preclinical research showed the drug could "coax" dormant cancer stem cells in hypoxic zones to begin differentiating and enter the bloodstream, where they can be attacked by the chemotherapy and the immune system.

In the study, researchers treated 47 adults with blood and marrow cancers with with the drug in 28-day cycles. Treatment cycles were continued with escalating doses until a participant experienced adverse effects with no improvement in their condition. The participants who did not have adverse reactions or serious side effects continued to receive treatment cycles of the drug.

Serious adverse effects were seen in only 3 of the participants, though 60 percent of the group experienced treatment-related problems. Nearly half the people in the study saw positive clinical activity as a result of treatment with vismedogib, the researchers said, and 5 Phase II clinical trials are being scheduled for the drug for use with blood cancer.

"This drug gets that unwanted house guests to leave and never come back," Jamieson said. "It's a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome and myelofibrosis. It's a bonus that the drug can be administered as easily as an aspirin, in a single, daily oral tablet."

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Date: 01 Aug 2015

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Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5M), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20M. We further revealed that TSA (1 and 5M) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

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The UCLA Program is a combined program caring for patients with Hematologic Malignancies receiving chemotherapy and those patients for whom Stem Cell Transplantation is the therapy of choice. The treatmentof blood and marrow cancers includecurrently available therapies, investigational drugs and treatments, as well as stem cell transplantation. Our physicians meet weekly to discussindividual treatment approachesas part of developing a coordinated treatment recommendation.

Bone Marrow Transplantation was first performed at UCLA in 1968 using a related allogeneic transplant to treat an 18 month old child with severe combined immunodeficiency syndrome. The UCLA Marrow Transplantation Program was formally initiated in 1973. Unrelated donor marrow transplants have been carried out at UCLA since 1987, and Cord Blood Transplants have been performed at UCLA since 1996. Autologous transplants have been performed at our program since 1977. Since 1992 most of the Autologous Transplants have utilized Peripheral Blood Stem Cells. Since 1998 an increasing number of the Allogenic Transplants have utilized Peripheral Blood Stem Cells. From inception to the completion of 2007 we have performed 3726 transplants (3080 transplants in the adult population and 646 in the pediatric population).

For decades, this comprehensive program has provided a full range of services as a local, regional, national, and international referral center for transplantations for selected malignancies:

Our goals include finding new and innovative treatments for malignancies and expanding the effectiveness and applicability of bone marrow transplantation through such means as biologic response modifiers, growth factors, and chemotherapeutic agents.

Protocols involving chemotherapy with or without radiation therapy for patients in remission or relapse are available using bone marrow or peripheral blood stem cells from allogeneic, autologous and unrelated donors.

A bone marrow transplant is a procedure that transplant healthy bone marrow into a patient whose bone marrow is not working properly. A bone marrow transplant may be done for several conditions including hereditary blood diseases, hereditary metabolic diseases, hereditary immune deficiencies, and various forms of cancer.

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The United Network for Organ Sharing (UNOS) provides a toll-free patient services lines to help transplant candidates, recipients, and family members understand organ allocation practices and transplantation data. You may also call this number to discuss problems you may be experiencing with your transplant center or the transplantation system in general. The toll-free patient services line number is 1-888-894-6361

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Mesenchymal stem cells, or MSCs, are multipotent stromal cells that can differentiate into a variety of cell types,[1] including: osteoblasts (bone cells),[2]chondrocytes (cartilage cells),[3]myocytes (muscle cells)[4] and adipocytes (fat cells). This phenomenon has been documented in specific cells and tissues in living animals and their counterparts growing in tissue culture.

While the terms mesenchymal stem cell and marrow stromal cell have been used interchangeably, neither term is sufficiently descriptive:

The youngest, most primitive MSCs can be obtained from the umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However the MSCs are found in much higher concentration in the Whartons jelly compared to the umbilical cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is easily obtained after the birth of the newborn, is normally thrown away, and poses no risk for collection. The umbilical cord MSCs have more primitive properties than other adult MSCs obtained later in life, which might make them a useful source of MSCs for clinical applications.

An extremely rich source for mesenchymal stem cells is the developing tooth bud of the mandibular third molar. While considered multipotent, they may prove to be pluripotent. The stem cells eventually form enamel, dentin, blood vessels, dental pulp, and nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection at 810 years of age before calcification, and minimal to no morbidity, they will probably constitute a major source for personal banking, research, and multiple therapies. These stem cells have been shown capable of producing hepatocytes.

Additionally, amniotic fluid has been shown to be a rich source of stem cells. As many as 1 in 100 cells collected during amniocentesis has been shown to be a pluripotent mesenchymal stem cell.[9]

Adipose tissue is one of the richest sources of MSCs. There are more than 500 times more stem cells in 1 gram of fat than in 1 gram of aspirated bone marrow. Adipose stem cells are actively being researched in clinical trials for treatment of a variety of diseases.

The presence of MSCs in peripheral blood has been controversial. However, a few groups have successfully isolated MSCs from human peripheral blood and been able to expand them in culture.[10] Australian company Cynata also claims the ability to mass-produce MSCs from induced pluripotent stem cells obtained from blood cells using the method of K. Hu et al.[11][12]

Mesenchymal stem cells are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria, and polyribosomes. The cells, which are long and thin, are widely dispersed and the adjacent extracellular matrix is populated by a few reticular fibrils but is devoid of the other types of collagen fibrils.[13][14]

The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical.[15] Furthermore, MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex-vivo. The cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers.[16]

MSCs have a great capacity for self-renewal while maintaining their multipotency. Beyond that, there is little that can be definitively said. The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes, and chondrocytes as well as myocytes and neurons. MSCs have been seen to even differentiate into neuron-like cells,[17][18] but there is lingering doubt whether the MSC-derived neurons are functional.[19] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical;[20] and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known.[citation needed]

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High levels of active TGF- in the bone marrow and abnormalities in bone remodeling are associated with multiple skeletal disorders. Genetic mutations in the TGF- signaling pathway cause premature activation of matrix latent TGF- and may manifest with various skeletal defects. There are additional diseases that result in high levels of active TGF-, which may contribute to the pathology. Here, we discuss how abnormal TGF- signaling results in uncoupled bone remodeling, mainly by loss of site-directed recruitment of MSCs that causes aberrant bone formation. Direct or indirect inhibition of TGF- signaling may provide potential therapeutic options for these disorders.

Genetic disorders. The critical role of TGF-1 in the reversal phase of bone remodeling is demonstrated by the range of skeletal disorders resulting from mutations in genes involved in TGF-1 signaling. Camurati-Engelmann disease (CED), characterized by a fusiform thickening of the diaphysis of the long bones and skull, is caused by mutations in TGFB1 that result in premature activation of TGF-1 (7174). Approximately 11 different TGFB1 mutations have been identified from families affected by CED (75, 76). All of the mutations are located in the region encoding LAP, either destabilizing LAP disulfide bridging or affecting secretion of the protein, both of which increase TGF-1 signaling, as confirmed by in vitro cell cultures and mouse models. Bone histology sections from patients with CED show decreased trabecular connectivity despite normal bone histomorphometric parameters with respect to osteoblast and osteoclast numbers (76, 77), suggestive of uncoupled bone remodeling. In vitro, the ratio of active to total TGF-1 in conditioned medium from cells expressing the CED mutant TGF-1 is significantly higher and enhances MSC migration (18). Targeted recruitment of MSCs to the bone-remodeling site is likely disrupted, secondary to loss of a TGF- gradient.

Elevations in TGF- signaling have also been observed in many genetic connective tissue disorders with craniofacial, skeletal, skin, and cardiovascular manifestations, including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). MFS is caused by mutations in fibrillin and often results in aortic dilation, myopia, bone overgrowth, and joint laxity. Fibrillin is deposited in the ECM and normally binds TGF-, rendering it inactive. In MFS, the decreased level of fibrillin enhances TGF- activity (78). LDS is caused by inactivating mutations in genes encoding TRI and TRII (79). Physical manifestations include arterial aneurysms, hypertelorism, bifid uvula/cleft palate, and bone overgrowth resulting in arachnodactyly, joint laxity, and scoliosis. Pathologic analyses of affected tissue suggest chronically elevated TGF- signaling, despite the inactivating mutation (79). The mechanism of enhanced TGF- signaling remains under investigation. SGS is caused by mutations in the v-ski avian sarcoma viral oncogene homolog (SKI; refs. 80, 81) and causes physical features similar to those of MFS plus craniosynostosis. SKI negatively regulates SMAD-dependent TGF- signaling by impeding SMAD2 and SMAD3 activation, preventing nuclear translocation of the SMAD4 complex, and inhibiting TGF- target gene output by competing with p300/CBP for SMAD binding and recruiting transcriptional repressor proteins, such as mSin3A and HDACs (8284).

The neurocutaneous syndrome neurofibromatosis type 1 (NF1) has been noted to have skeletal features similar to those of CED, MFS, and LDS, including kyphoscoliosis, osteoporosis, and tibial pseudoarthrosis. Hyperactive TGF-1 signaling has been implicated as the primary factor underlying the pathophysiology of the osseous defects in Nf1fl/Col2.3Cre mice, a model of NF1 that closely recapitulates the skeletal abnormalities found in human disease (85). The exact mechanisms mediating mutant neurofibrominassociated enhancement of TGF- production and signaling remain unknown.

Osteoarthritis. While genetic disorders are rare, they have provided critical insight into the pathophysiology of more common disorders. Uncoupled bone remodeling accompanies the onset of osteoarthritis. TGF-1 is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis (86). High levels of active TGF-1 induced formation of nestin+ MSC clusters via activation of ALK5-SMAD2/3. MSCs underwent osteoblast differentiation in these clusters, leading to formation of marrow osteoid islets. Transgenic expression of active TGF-1 in osteoblastic cells alone was sufficient to induce osteoarthritis, whereas direct inhibition of TGF- activity in subchondral bone attenuated the degeneration of articular cartilage. Knockout of Tgfbr2 in nestin+ MSCs reduced osteoarthritis development after ACLT compared with wild-type mice, which confirmed that MSCs are the target cell population of TGF- signaling. High levels of active TGF-1 in subchondral bone likely disrupt the TGF- gradient and interfere with targeted migration of MSCs. Furthermore, mutations of ECM proteins that bind to latent TGF-s, such as small leucine-rich proteoglycans (87) and fibrillin (88), or mutations in genes involved in activation of TGF-, such as in CED (76) and LDS (89), are associated with high osteoarthritis incidence. Osteoblast differentiation of MSCs in aberrant locations appears histologically as subchondral bone osteoid islets and alters the thickness of the subchondral plate and calcified cartilage zone, changes known to be associated with osteoarthritis (90, 91). A computer-simulated model found that a minor increase in the size of the subchondral bone (1%2%) causes significant changes in the mechanical load properties on articular cartilage, which likely leads to degeneration (86). Importantly, inhibition of the TGF- signaling pathway delayed the development of osteoarthritis in both mouse and rat models (86).

MSCs in bone loss. Aging leads to deterioration of tissue and organ function. Skeletal aging is especially dramatic: bone loss in both women and men begins as early as the third decade, immediately after peak bone mass. Aging bone loss occurs when bone formation does not adequately compensate for osteoclast bone resorption during remodeling. Age-associated osteoporosis was previously believed to be due to a decline in survival and function of osteoblasts and osteoprogenitors; however, recent work by Park and colleagues found that mature osteoblasts and osteoprogenitors are actually nonreplicative cells and require constant replenishment from bone marrow MSCs (92). When MSCs fail to migrate to bone-resorptive sites or are unable to commit and differentiate into osteoblasts, new bone formation is impaired. Therefore, insufficient recruitment of MSCs, or their differentiation to osteoblasts, at the bone remodeling surface may contribute to the decline in bone formation in the elderly.

There are multiple hypotheses regarding the decreased osteogenic potential of MSCs during aging. For example, during aging, the bone marrow environment has an increased concentration of ROS and lipid oxidation that may decrease osteoblast differentiation, yet increase osteoclast activity (93, 94). MSCs also undergo senescence, which decreases proliferative capacity and contributes to decreased bone formation (95, 96). Cellular senescence involves the secretion of a plethora of factors, including TGF-, which induces expression of cyclin-dependent kinase inhibitors 2A and 2B (p16INK4A and p15INK4B, respectively; refs. 97).

Microgravity experienced by astronauts during spaceflight causes severe physiological alterations in the human body, including a 1%2% loss of bone mass every month during spaceflight (98). Several studies have shown decreases in osteoblastic markers of bone formation and increases in bone resorption (99101). The underlying molecular mechanisms responsible for the apparent concurrent decrease in bone formation and increase in bone resorption remain under investigation. Work by the McDonald group suggests that bone remodeling may become uncoupled under zero-gravity conditions secondary to decreased RhoA activity and resultant changes in actin stress fiber formation (102). In modeled microgravity, cultured human MSCs exhibit disruption of F-actin stress fibers within three hours of initiation of microgravity; the fibers are completely absent after seven days. RhoA activity is significantly reduced, and introduction of an adenoviral construct expressing constitutively active RhoA can reverse the elimination of stress fibers, significantly increasing markers of osteoblast differentiation (102). Under zero-gravity conditions, RhoA is unable to bind to its receptor, and a sufficient number of MSCs may not be able to migrate correctly to the bone-resorptive site for osteoblast differentiation, ultimately leading to bone loss with every cycle of remodeling.

Bone metastases are a frequent complication of cancer and often have both osteolytic and osteoblastic features, indicative of dysregulated bone remodeling. The importance of the bone marrow microenvironment contributing to the spread of cancer was first described in 1889 (103), postulating that tumor cells can grow only if they are in a conducive environment. Activation of matrix TGF- during bone remodeling plays a central role in the initiation of bone metastases and tumor expansion by regulating osteolytic and prometastatic factors (reviewed in refs. 104110). For example, TGF- can induce osteoclastic bone destruction by upregulating tumor cell expression of PTHrP and IL-11. Additionally, upregulation of CXCR4 by TGF- may home cancer cells to bones.

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Haematopoietic stem cells and early lymphoid progenitors ...

You will have a low white blood cell count after your treatment. This means you are more at risk of getting an infection. You are likely to get an infection from the normally harmless bacteria we all have in our digestive systems and on our skin.

To stop this from happening your nurse may give you tablets called gut sterilisers (antibiotics) and mouthwashes. And they will encourage you to have a shower each day.

You are also at risk of infection from food. The nurses on the ward will tell you and your relatives about the food you can and can't eat. The rules vary from hospital to hospital but you may be told that

Your room will be thoroughly cleaned every day. Your visitors will be asked to wash their hands before they come into your room. They may also have to wear disposable gloves and aprons. Visitors with coughs and colds are not allowed. Some hospitals don't allow you to have plants or flowers in your room because bacteria and fungi can grow in the soil or water, and may cause infection.

Even with all these precautions, most people do get an infection at some point and need to have antibiotics. You can help yourself by trying to do your mouth care properly and getting up to shower and have your bed changed even on the days you don't feel too good.

After a transplant you will have lost immunity to diseases you were vaccinated against as a child. The team caring for you will advise you about the immunisations you need and when. You should only have inactivated immunisations and not live ones. To lower the risk of you getting any of these infections it is important that all your family have the flu vaccine and any children have all their immunisations.

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Side effects of bone marrow and stem cell transplants ...

With Brigham and Womens Hospital and Boston Childrens Hospital, Dana-Farber has performed thousands of stem cell/bone marrow transplants for adult and pediatric patients with blood cancers and other serious illnesses.

Whats the difference between these two terms? As it turns out, the only real distinction is in the method of collecting the stem cells.

Lets start with the basics.

Stem cells are versatile cells with the ability to divide and develop into many other kinds of cells.

Hematopoietic stem cells produce red blood cells, which deliver oxygen throughout the body; white blood cells, which help ward off infections; and platelets, which allow blood to clot and wounds to heal.

While chemotherapy and/or radiation therapy are essential treatments for the majority of cancer patients, high doses can severely weakenand even wipe outhealthy stem cells. Thats where stem cell transplantation comes in.

Stem cell transplantation is a general term that describes the procedures performed by the Adult Stem Cell Transplantation Program at Dana-Farber/Brigham and Womens Cancer Center and the Pediatric Stem Cell Transplantation Program at Dana-Farber/Boston Childrens Cancer and Blood Disorders Center.

Stem cells for transplant can come from bone marrow or blood.

When stem cells are collected from bone marrow and transplanted into a patient, the procedure is known as a bone marrow transplant. If the transplanted stem cells came from the bloodstream, the procedure is called a peripheral blood stem cell transplantsometimes shortened to stem cell transplant.

Whether you hear someone talking about a stem cell transplant or a bone marrow transplant, they are still referring to stem cell transplantation. The only difference is where in the body the transplanted stem cells came from. The transplants themselves are the same.

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Stem Cell vs. Bone Marrow Transplant: Whats the ...

Introduction: What are stem cells, and why are they important? What are the unique properties of all stem cells? What are embryonic stem cells? What are adult stem cells? What are the similarities and differences between embryonic and adult stem cells? What are induced pluripotent stem cells? What are the potential uses of human stem cells and the obstacles that must be overcome before these potential uses will be realized? Where can I get more information?

Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions.

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. The functions and characteristics of these cells will be explained in this document. Scientists discovered ways to derive embryonic stem cells from early mouse embryos more than 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell-like state. This new type of stem cell, called induced pluripotent stem cells (iPSCs), will be discussed in a later section of this document.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lungs, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

I.Introduction|Next

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Stem Cell Basics: Introduction [Stem Cell Information]

Having someone elses marrow or stem cells is called a donor transplant, or an allogeneic transplant. This is pronounced al-lo-jen-ay-ik.

The donors bone marrow cells must match your own as closely as possible. The most suitable donor is usually a close relative, such as a brother or sister. It is sometimes possible to find a match in an unrelated donor. Doctors call this a matched unrelated donor (MUD). To find out if there is a suitable donor for you, your doctor will contact The Anthony Nolan Bone Marrow Register and other UK based and international bone marrow registers.

To make sure that your donors cells match, you and the donor will have blood tests. These are to see how many of the proteins on the surface of their blood cells match yours. This is called tissue typing or HLA matching. HLA stands for human leucocyte antigen.

Once you have a donor and are in remission, you have high dose chemotherapy either on its own or with radiotherapy. A week later the donor goes into hospital and their stem cells or marrow are collected. You then have the stem cells or bone marrow as a drip through your central line.

If you've had a transplant from a donor, there is a risk of graft versus host disease (GVHD). This happens because the transplanted stem cells or bone marrow contain cells from your donor's immune system. These cells can sometimes recognise your own tissues as being foreign and attack them. This can be an advantage because the immune cells may also attack any leukaemia cells left after your treatment.

Acute GVHD starts within 100 days of the transplant and can cause

If you develop GVHD after your transplant, your doctor will prescribe medicines to damp down this immune reaction. These are called immunosuppressants.

Chronic GVHD starts more than 100 days after the transplant and you may have

Your doctor is likely to suggest that you stay out of the sun because GVHD skin rashes can often get worse in the sun.

There is detailed information about graft versus host disease in the section about coping physically with cancer.

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Bone marrow or stem cell transplants for AML | Cancer ...

With more than 50 years of experience studying blood-forming stem cells called hematopoietic stem cells, scientists have developed sufficient understanding to actually use them as a therapy. Currently, no other type of stem cell, adult, fetal or embryonic, has attained such status. Hematopoietic stem cell transplants are now routinely used to treat patients with cancers and other disorders of the blood and immune systems. Recently, researchers have observed in animal studies that hematopoietic stem cells appear to be able to form other kinds of cells, such as muscle, blood vessels, and bone. If this can be applied to human cells, it may eventually be possible to use hematopoietic stem cells to replace a wider array of cells and tissues than once thought.

Despite the vast experience with hematopoietic stem cells, scientists face major roadblocks in expanding their use beyond the replacement of blood and immune cells. First, hematopoietic stem cells are unable to proliferate (replicate themselves) and differentiate (become specialized to other cell types) in vitro (in the test tube or culture dish). Second, scientists do not yet have an accurate method to distinguish stem cells from other cells recovered from the blood or bone marrow. Until scientists overcome these technical barriers, they believe it is unlikely that hematopoietic stem cells will be applied as cell replacement therapy in diseases such as diabetes, Parkinson's Disease, spinal cord injury, and many others.

Blood cells are responsible for constant maintenance and immune protection of every cell type of the body. This relentless and brutal work requires that blood cells, along with skin cells, have the greatest powers of self-renewal of any adult tissue.

The stem cells that form blood and immune cells are known as hematopoietic stem cells (HSCs). They are ultimately responsible for the constant renewal of bloodthe production of billions of new blood cells each day. Physicians and basic researchers have known and capitalized on this fact for more than 50 years in treating many diseases. The first evidence and definition of blood-forming stem cells came from studies of people exposed to lethal doses of radiation in 1945.

Basic research soon followed. After duplicating radiation sickness in mice, scientists found they could rescue the mice from death with bone marrow transplants from healthy donor animals. In the early 1960s, Till and McCulloch began analyzing the bone marrow to find out which components were responsible for regenerating blood [56]. They defined what remain the two hallmarks of an HSC: it can renew itself and it can produce cells that give rise to all the different types of blood cells (see Chapter 4. The Adult Stem Cell).

A hematopoietic stem cell is a cell isolated from the blood or bone marrow that can renew itself, can differentiate to a variety of specialized cells, can mobilize out of the bone marrow into circulating blood, and can undergo programmed cell death, called apoptosisa process by which cells that are detrimental or unneeded self-destruct.

A major thrust of basic HSC research since the 1960s has been identifying and characterizing these stem cells. Because HSCs look and behave in culture like ordinary white blood cells, this has been a difficult challenge and this makes them difficult to identify by morphology (size and shape). Even today, scientists must rely on cell surface proteins, which serve, only roughly, as markers of white blood cells.

Identifying and characterizing properties of HSCs began with studies in mice, which laid the groundwork for human studies. The challenge is formidable as about 1 in every 10,000 to 15,000 bone marrow cells is thought to be a stem cell. In the blood stream the proportion falls to 1 in 100,000 blood cells. To this end, scientists began to develop tests for proving the self-renewal and the plasticity of HSCs.

The "gold standard" for proving that a cell derived from mouse bone marrow is indeed an HSC is still based on the same proof described above and used in mice many years ago. That is, the cells are injected into a mouse that has received a dose of irradiation sufficient to kill its own blood-producing cells. If the mouse recovers and all types of blood cells reappear (bearing a genetic marker from the donor animal), the transplanted cells are deemed to have included stem cells.

These studies have revealed that there appear to be two kinds of HSCs. If bone marrow cells from the transplanted mouse can, in turn, be transplanted to another lethally irradiated mouse and restore its hematopoietic system over some months, they are considered to be long-term stem cells that are capable of self-renewal. Other cells from bone marrow can immediately regenerate all the different types of blood cells, but under normal circumstances cannot renew themselves over the long term, and these are referred to as short-term progenitor or precursor cells. Progenitor or precursor cells are relatively immature cells that are precursors to a fully differentiated cell of the same tissue type. They are capable of proliferating, but they have a limited capacity to differentiate into more than one cell type as HSCs do. For example, a blood progenitor cell may only be able to make a red blood cell (see Figure 5.1. Hematopoietic and Stromal Stem Cell Differentiation).

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5. Hematopoietic Stem Cells [Stem Cell Information]

A new study from the Forsyth Institute is helping to shed light on latent tuberculosis and the bacteria's ability to hide in stem cells. Some bone marrow stem cells reside in low oxygen (hypoxia) zones. These specialized zones are secured as immune cells and toxic chemicals cannot reach this zone. Hypoxia- activated cell signaling pathways may also protect the stem cells from dying or ageing. A new study led by Forsyth Scientist Dr. Bikul Das has found that Mycobacterium tuberculosis (Mtb) hijack this protective hypoxic zone to hide intracellular to a special stem cell type. The study was published online on June 8th in the American Journal of Pathology.

Mtb, the causative organism of tuberculosis, infects nearly 2.2 billion people worldwide and causes 1.7 million annual deaths. This is largely attributed to the bacteria's ability to stay dormant in the human body and later resurface as active disease. Earlier research at Forsyth revealed that Mtb hides inside a specific stem cell population in bone marrow, the CD271+ mesenchymal stem cells. However, the exact location of the Mtb harboring stem cells was not known.

"From our previous research, we learned that cancer stem cells reside in the hypoxic zones to maintain self-renewal property, and escape from the immune system" said Bikul Das, MBBS, PhD, Associate Research Investigator at the Forsyth Institute, and the honorary director of the KaviKrishna laboratory, Guwahati, India. "So, we hypothesized that Mtb, like cancer, may also have figured out the advantage of hiding in the hypoxic area."

To test this hypothesis, Dr. Das and his collaborators at Jawarharlal Nehru Univeristy (JNU), New Delhi, and KaviKrishna Laboratory, Indian Institute of Technology, Guwahati, utilized a well-known mouse model of Mtb infection, where months after drug treatment, Mtb remain dormant for future reactivation. Using this mouse model of dormancy, scientists isolated the special bone marrow stem cell type, the CD271+ mesenchymal stem cells, from the drug treated mice. Prior to isolation of the stem cells, mice were injected with pimonidazole, a chemical that binds specifically to hypoxic cells. Pimonidazole binding of these cells was visualized under confocal microscope and via flow cytometry. The scientists found that despite months of drug treatment, Mtb could be recovered from the CD271+ stem cells. Most importantly, these stem cells exhibit strong binding to pimonidazole, indicating the hypoxic localization of the stem cells. Experiments also confirmed that these stem cells express a hypoxia activated gene, the hypoxia inducible factor 1 alpha (HIF-1 alpha).

To confirm the findings in clinical subjects, the research team, in collaboration with KaviKrishna Laboratory, the team isolated the CD271+ stem cell type from the bone marrow of TB infected human subjects who had undergone extensive treatment for the disease. They found that not only did the stem cell type contain viable Mtb, but also exhibit strong expression of HIF-1alpha. To their surprise, the CD271+ stem cell population expressed several fold higher expression of HIF-1alpha than the stem cell type obtained from the healthy individuals.

"These findings now explain why it is difficult to develop vaccines against tuberculosis," said Dr. Das. "The immune cells activated by the vaccine agent may not be able to reach the hypoxic site of bone marrow to target these "wolfs-in-stem-cell-clothing".

The success of this international collaborative study is now encouraging the team to develop a Forsyth Institute/KaviKrishna Laboratory global health research initiative to advance stem cell research and its application to global health issues including TB, HIV and oral cancer, all critical problems in the area where KaviKrishna Laboratory is located.

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Das is the co-senior and co-corresponding author of the study, Rakesh Bhatnagar, PhD, professor of biotechnology, JNU, New Delhi, is the co-senior author of the study. Ms. Jaishree Garhain, a PhD student of Dr. Das and Dr. Bhatnagar, is the first author of the study. Other members of the team are Ms. Seema Bhuyan, Dr. Deepjyoti Kalita, and Dr. Ista Pulu. The research was funded by the KaviKrishna Foundation (Sualkuchi, India), the Laurel Foundation (Pasadena, California), and Department of Biotechnology, India.

About The Forsyth Institute

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Tuberculosis bacteria hide in the low oxygen niches of ...

Bone Marrow Stem Cells

Dr. Steenblock performing a bone marrow stem cell treatment

The latest discovery in the world of natural medical therapies is STEM CELLS!

You have within you a powerful set of tools to repair your body and keep you healthy. The future of medicine is NOT better drugs but better use and application of your bodys own stem cells. As of now stem cell-rich tissue can be extracted from your hip with virtually no discomfort and used to help restore your body. This opens up an exciting new horizon in terms of preventing and treating disease and tackling the symptoms of aging if not aging itself. Already, patients are returning to Dr. Steenblock for additional bone marrow treatments because they are seeing that their gray or white hair is turning back to its original color. Their skin not infrequently looks younger too and they report having more energy and less arthritic aches and pains!

Over the past six years, Dr. Steenblock and his medical team have done over 2,000 bone marrow procedures with much success. Contrary to the conventional painful methods used, he and his colleagues have developed an almost painless approach to extract bone marrow and the hidden trove of stem cells contained within. Using the patients own bone marrow rather than someone elses has totally eliminated the risk of graft versus host disease and the need for toxic chemotherapy to suppress the immune system. Since Dr. Steenblock is merely transferring stem cells from a persons bones into their blood stream there is never an allergic or rejection type of reaction since these are the patients own cells. The results have at times been phenomenal especially for those under 40 and for those who are really physically fit and walk or run a lot every day. The stronger an individuals bones are the better the bone marrow stem cells are. Even children that are paralyzed and who do not put weight on their legs are generally not going to have good results unless add another facet is added to their treatment. For those people who do not walk much, are not physically fit and who are older than 40, Dr. Steenblock generally recommends that they undergo five successive daily injections of a natural bone marrow mobilizer called Neupogen (Filgrastim) beginning 19 days before they come to his office for their bone marrow treatment(s). The ideal treatment for anyone with a complicated health issue is to first have certain tests done to determine if they have any problems that could interfere with the treatments success. These tests include standard blood tests for anemia, hormones, metabolism, infections, autoimmunity, inflammation and special tests for heavy metal poisons and intestinal infections and infestations. If problems are discovered with these tests then the underlying problem should be corrected before beginning the process of using the Neupogen and the scheduling of the bone marrow treatment(s). The word marrows is pleural intentionally because a person in general has a better result if more stem cells are given. By having two bone marrow procedures on successive days an individual will double the number of stem cells they receive. For example, if a 60 year old sedentary person comes in and does only one bone marrow treatment Dr. Steenblock will generally extract about 400 milliliters of stem cell-rich bone marrow (buffy coat after centrifugation) which is put directly back into the blood stream by intravenous means. The number of active, healthy stem cells in this simple procedure may only be 100 million and these in general will not be as healthy or as active as they will be if the patient first has any known or potential impediments to their post-infusion activity eliminated and they are given the 5 daily injections of Neupogen. When a person comes to the clinic 14 days after their last Neupogen injection, that same 400 ml of bone marrow will have somewhere between 500 and 1000 million stem cells and then if they repeat the process the next day they will get another 500-1000 million stem cells. By this combination of eradicating infections, correcting other problems discovered using our testing, and then using Neupogen followed by two bone marrow treatments patients will be receiving well over a billion stem cells.

Benefits of Bone Marrow Stem Cells

What is the secret behind the successes Dr. Steenblock has seen with the bone marrow treatments? While bone marrow transplants have been done for the past 50 years for cancer patients and those with blood disorders, the whole bone marrow procedure done by Dr. Steenblock is different because it is so SIMPLE! He uses a persons own bone marrow and instead of isolating one type of stem cell, he takes and uses the whole raw bone marrow which contains a rich variety of stem and progenitor cells. In fact, bone marrow is rich in two different types of stem cells: One type turns into blood cells, blood vessels, and cells of the immune system and are called hematopoietic stem cells (heme meaning blood-related). The other type of stem cell is the support (stromal or mesenchymal) stem cell that produces bone, fat, tendons, skin, muscles and connective tissue. Recent research shows that these hematopoietic and the support stem cells are also able to divide into all types of brain cells, including glial cells (white matter) and neurons (gray matter). The bone marrow also contains retinal progenitor cells and several patients have actually commented on how their vision improved as a side benefit of their bone marrow procedure. These two type of stem cells work better together in a ratio of one hematopoietic to 4 to 8 support (stromal or mesenchymal) stem cells which is the ratio found normally in most peoples bone marrow.

In regard to its anti-aging effects, the bone marrow contains primitive progenitor cells that are associated with the early development of the fetus. These primitive cells reside dormant deep inside each of our bones and sport a virginal profile from early development in that these stem cells are generally resting and not active. This inactivity protects them from chemicals or stresses that induce mutations such as occurs in those bone marrow stem cells that are located in the more superficial areas of the bone which are constantly making red and white blood cells. When these primitive, more pure cells are released into a persons system, there can be a revitalization of the body that physiologically sets the clock back in-a-way since these stem cells get into all parts of the body and produce more growth factors than would otherwise be possible. It is this increase in growth factors that induces the regenerative processes. For those that can afford it Dr. Steenblock uses growth factors oriented toward improving the organs that are diseased. For example, if a patients chief problem is their lungs then he may suggest some lung growth factors to be taken right along with the Neupogen and then continued for 6 weeks to help push the stem cells into becoming more like lung tissue cells.

Bottom line: Bone marrow stem cells have the potential to repair damaged tissues and organs. Whether a person wants an anti-aging treatment or needs the procedure to repair damage in joints, liver, kidneys, heart or brain, bone marrow transplants is an efficient and sure way to flood their body with stem cells.

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bone marrow stem cells - Stem Cells Adult Stem Cells ...

Bone marrow stem cells

Diseases such as aplastic anaemia, or infections (such as tuberculosis) can negatively impact the ability of the bone marrow to produce blood cells or platelets. Other diseases, such as leukaemia, also affect the progenitor/stem cells in the bone marrow and are diagnosed by a bone marrow biopsy where a sample of the tissue is taken using a large hollow needle inserted into the iliac crest (the pelvic bone). Harvesting bone marrow is usually done under general anaesthetic, although local anaesthetic is also a possibility.

Recent advances in stimulating and harvesting stem cells from the peripheral blood may mean that the invasiveness of bone marrow harvesting can be avoided for some donors and patients. Stimulatory pharmaceuticals, such as GM-CSF, and G-CSF, which drive the stem cells out of the bone marrow and into the peripheral circulation, can allow for a large yield of stem cells during apheresis. However, bone marrow stem cells have been found through research in the past five years or so to be able to differentiate into more cell types than previously thought. Mesenchymal stem cells from bone marrow have been successfully cultured to create beta-pancreatic cells, and neural cells, with possible ramifications for treatment of diabetes and neurodegenerative diseases. Clinical trials involving stem cell treatments for such conditions in humans remain theoretical however as there are a number of issues that need further investigation to confirm efficacy and safety.

The stem cells contained within bone marrow are of three types; haematopoietic stem cells, mesenchymal stem cells, and endothelial stem cells. Haematopoietic stem cells differentiate into both white and red blood cells, and platelets. These leukocytes, erythrocytes, and thrombocytes, respectively, play a role in immune function, oxygen transportation, and blood-clotting and are destroyed by chemotherapy for cancers such as leukaemia. This is why bone marrow transplants can mean the difference between life and death for someone suffering from such a disease as it is vital to replace and repopulate the bone marrow with stem cells that can then create new blood- and immune-forming cells.

Mesenchymal stem cells are also found in the bone marrow and are responsible for creating osteoblasts, chrondrocytes, and mycocytes, along with a number of other cell types. The location of these stem cells differs from that of the haematopoietic stem cells as they are usually central to the bone marrow, which makes it easier to extract specific populations of stem cells during a bone marrow aspiration procedure.

Bone marrow mesenchymal stem cells have also been found to differentiate into beta-pancreatic islet cells, with potential ramifications for treating those with diabetes (Moriscot, et al, 2005). Neural-like cells have also been cultured from bone marrow mesenchymal stem cells making the bone marrow a possible source for stem cell treatment of neurological disorders (Hermann, et al, 2006). More recent research appears to show that donor-heterogeneity (genetic differences between those donating the bone marrow) is at the heart of the variability in mesenchymal stem cells ability to differentiate to neural cells (Montzka, et al, 2009). This means that careful selection of donor stem cells would have to be carried out in order for treatment to be successful if the research ever displays clinical significance. Conditions such as spinal cord injury, Alzheimers Disease, and Multiple Sclerosis, may be able to be treated in the future using mesenchymal stem cells from bone marrow that were previously thought to only be able to produce bone and cartilage cell types.

Patients with leukaemia or other cancer are likely to be treated with radiation and/or chemotherapy. Both of these treatements kill the stem cells in the bone marrow to some degree and it is the effect that this has on the immune system that is responsible for many of the symptoms of chemotherapy and radiation sickness. In some cases, a patient with cancer may have bone marrow harvested and some stem cells stored prior to radiation treatment or chemotherapy. They then have their own stem cells infused after the cancer treatment in order to repopulate their immune system. This presents little risk of graft versus host disease which is a concern with, non-autologous, allograft bone marrow transplants. The use of a patients own stem cells is unlikely to be helpful in cases where an in-borne mutation of the blood and lymph system is present and such procedures are not usually performed in such cases.

Bone marrow transplantation from a donor source will normally require the destruction of the patients own bone marrow in a process called myeloablation. Patients who undergo myeloablation will lose their acquired immunity and are usually advised to undergo all vaccinations for diseases such as mumps, measles, rubella, and so on. Myeloablation also means that the patient has extremely low white blood cell (leukocyte) levels for a number of weeks as the bone marrow stem cells begin to create new blood and immune system cells. Patients undergoing this procedure are, therefore, extremely susceptible to infection and complication making bone marrow transplants only appropriate in life-threatening situations. Many patients will take antibiotics during this time in an attempt to avoid sepsis, infections, and septic shock. Some patients will be given immunosuppressant drugs to lower the risk of graft versus host disease and this can make them even more susceptible to infection.

It is also possible that the new stem cells do not engraft, which means that they do not begin to create new blood and immune-system cells at all. Peripheral blood stem cells harvested at the same time as bone marrow harvesting were found in one study to speed the recovery of the patients immune systems following myeloablation, thus reducing the risk if infection (Rabinowitz, et al, 1993). Peripheral blood stem cells do appear to be quicker in general at engrafting and they may become more widely involved in the treatment of diseases traditionally addressed through bone marrow transplants (Lewis, 2005).

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Bone Marrow Stem Cells - Stem Cell Research

by Jos Domen*, Amy Wagers** and Irving L. Weissman***

Blood and the system that forms it, known as the hematopoietic system, consist of many cell types with specialized functions (see Figure 2.1). Red blood cells (erythrocytes) carry oxygen to the tissues. Platelets (derived from megakaryocytes) help prevent bleeding. Granulocytes (neutrophils, basophils and eosinophils) and macrophages (collectively known as myeloid cells) fight infections from bacteria, fungi, and other parasites such as nematodes (ubiquitous small worms). Some of these cells are also involved in tissue and bone remodeling and removal of dead cells. B-lymphocytes produce antibodies, while T-lymphocytes can directly kill or isolate by inflammation cells recognized as foreign to the body, including many virus-infected cells and cancer cells. Many blood cells are short-lived and need to be replenished continuously; the average human requires approximately one hundred billion new hematopoietic cells each day. The continued production of these cells depends directly on the presence of Hematopoietic Stem Cells (HSCs), the ultimate, and only, source of all these cells.

Figure 2.1. Hematopoietic and stromal cell differentiation.

2001 Terese Winslow (assisted by Lydia Kibiuk)

The search for stem cells began in the aftermath of the bombings in Hiroshima and Nagasaki in 1945. Those who died over a prolonged period from lower doses of radiation had compromised hematopoietic systems that could not regenerate either sufficient white blood cells to protect against otherwise nonpathogenic infections or enough platelets to clot their blood. Higher doses of radiation also killed the stem cells of the intestinal tract, resulting in more rapid death. Later, it was demonstrated that mice that were given doses of whole body X-irradiation developed the same radiation syndromes; at the minimal lethal dose, the mice died from hematopoietic failure approximately two weeks after radiation exposure.1 Significantly, however, shielding a single bone or the spleen from radiation prevented this irradiation syndrome. Soon thereafter, using inbred strains of mice, scientists showed that whole-body-irradiated mice could be rescued from otherwise fatal hematopoietic failure by injection of suspensions of cells from blood-forming organs such as the bone marrow.2 In 1956, three laboratories demonstrated that the injected bone marrow cells directly regenerated the blood-forming system, rather than releasing factors that caused the recipients' cells to repair irradiation damage.35 To date, the only known treatment for hematopoietic failure following whole body irradiation is transplantation of bone marrow cells or HSCs to regenerate the blood-forming system in the host organisms.6,7

The hematopoietic system is not only destroyed by the lowest doses of lethal X-irradiation (it is the most sensitive of the affected vital organs), but also by chemotherapeutic agents that kill dividing cells. By the 1960s, physicians who sought to treat cancer that had spread (metastasized) beyond the primary cancer site attempted to take advantage of the fact that a large fraction of cancer cells are undergoing cell division at any given point in time. They began using agents (e.g., chemical and X-irradiation) that kill dividing cells to attempt to kill the cancer cells. This required the development of a quantitative assessment of damage to the cancer cells compared that inflicted on normal cells. Till and McCulloch began to assess quantitatively the radiation sensitivity of one normal cell type, the bone marrow cells used in transplantation, as it exists in the body. They found that, at sub-radioprotective doses of bone marrow cells, mice that died 1015 days after irradiation developed colonies of myeloid and erythroid cells (see Figure 2.1 for an example) in their spleens. These colonies correlated directly in number with the number of bone marrow cells originally injected (approximately 1 colony per 7,000 bone marrow cells injected).8 To test whether these colonies of blood cells derived from single precursor cells, they pre-irradiated the bone marrow donors with low doses of irradiation that would induce unique chromosome breaks in most hematopoietic cells but allow some cells to survive. Surviving cells displayed radiation-induced and repaired chromosomal breaks that marked each clonogenic (colony-initiating) hematopoietic cell.9 The researchers discovered that all dividing cells within a single spleen colony, which contained different types of blood cells, contained the same unique chromosomal marker. Each colony displayed its own unique chromosomal marker, seen in its dividing cells.9 Furthermore, when cells from a single spleen colony were re-injected into a second set of lethally-irradiated mice, donor-derived spleen colonies that contained the same unique chromosomal marker were often observed, indicating that these colonies had been regenerated from the same, single cell that had generated the first colony. Rarely, these colonies contained sufficient numbers of regenerative cells both to radioprotect secondary recipients (e.g., to prevent their deaths from radiation-induced blood cell loss) and to give rise to lymphocytes and myeloerythroid cells that bore markers of the donor-injected cells.10,11 These genetic marking experiments established the fact that cells that can both self-renew and generate most (if not all) of the cell populations in the blood must exist in bone marrow. At the time, such cells were called pluripotent HSCs, a term later modified to multipotent HSCs.12,13 However, identifying stem cells in retrospect by analysis of randomly chromosome-marked cells is not the same as being able to isolate pure populations of HSCs for study or clinical use.

Achieving this goal requires markers that uniquely define HSCs. Interestingly, the development of these markers, discussed below, has revealed that most of the early spleen colonies visible 8 to 10 days after injection, as well as many of the later colonies, visible at least 12 days after injection, are actually derived from progenitors rather than from HSCs. Spleen colonies formed by HSCs are relatively rare and tend to be present among the later colonies.14,15 However, these findings do not detract from Till and McCulloch's seminal experiments to identify HSCs and define these unique cells by their capacities for self-renewal and multilineage differentiation.

While much of the original work was, and continues to be, performed in murine model systems, strides have been made to develop assays to study human HSCs. The development of Fluorescence Activated Cell Sorting (FACS) has been crucial for this field (see Figure 2.2). This technique enables the recognition and quantification of small numbers of cells in large mixed populations. More importantly, FACS-based cell sorting allows these rare cells (1 in 2000 to less than 1 in 10,000) to be purified, resulting in preparations of near 100% purity. This capability enables the testing of these cells in various assays.

Figure 2.2. Enrichment and purification methods for hematopoietic stem cells. Upper panels illustrate column-based magnetic enrichment. In this method, the cells of interest are labeled with very small iron particles (A). These particles are bound to antibodies that only recognize specific cells. The cell suspension is then passed over a column through a strong magnetic field which retains the cells with the iron particles (B). Other cells flow through and are collected as the depleted negative fraction. The magnet is removed, and the retained cells are collected in a separate tube as the positive or enriched fraction (C). Magnetic enrichment devices exist both as small research instruments and large closed-system clinical instruments.

Lower panels illustrate Fluorescence Activated Cell Sorting (FACS). In this setting, the cell mixture is labeled with fluorescent markers that emit light of different colors after being activated by light from a laser. Each of these fluorescent markers is attached to a different monoclonal antibody that recognizes specific sets of cells (D). The cells are then passed one by one in a very tight stream through a laser beam (blue in the figure) in front of detectors (E) that determine which colors fluoresce in response to the laser. The results can be displayed in a FACS-plot (F). FACS-plots (see figures 3 and 4 for examples) typically show fluorescence levels per cell as dots or probability fields. In the example, four groups can be distinguished: Unstained, red-only, green-only, and red-green double labeling. Each of these groups, e.g., green fluorescence-only, can be sorted to very high purity. The actual sorting happens by breaking the stream shown in (E) into tiny droplets, each containing 1 cell, that then can be sorted using electric charges to move the drops. Modern FACS machines use three different lasers (that can activate different set of fluorochromes), to distinguish up to 8 to 12 different fluorescence colors and sort 4 separate populations, all simultaneously.

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2. Bone Marrow (Hematopoietic) Stem Cells [Stem Cell ...

Key Messages:

Although a stem cell transplant (sometimes called a bone marrow transplant) is an effective treatment for several types of cancer, it can cause a number of different side effects. The type and intensity of these side effects vary from person to person and depend on the kind of transplant performed, the person's overall health, and other factors. Your health care team will work with you to prevent side effects or manage any that occur. This is called palliative or supportive care and is an important part of your overall treatment plan. Be sure to talk with your health care team about any side effects you experience, including new symptoms or a change in symptoms.

The two most serious side effects of stem cell transplantation are infection and graft-versus-host disease.

Infection

The chemotherapy and/or radiation therapy given before a stem cell transplant weakens a persons immune system, lowering the bodys defenses against bacteria, viruses, and fungi. That means stem cell recipients are especially vulnerable to infection during this early period of treatment.

Although most people think the greatest risk of infection is from visitors or food, most infections that occur during the first few weeks after a transplant are caused by organisms that are already in the patient's lungs, sinuses, skin, and intestines. Fortunately, most of these infections are relatively easy to treat with antibiotics.

The reduced immunity of the early transplant period lasts about two weeks, after which the immune system is back to near full strength and can keep most common germs at bay without the help of medications. This is true for both autologous (AUTO) transplant recipients (who receive their own stem cells) and allogeneic (ALLO) transplant recipients (who receive stem cells from another person).

However, a risk of serious infection remains for ALLO transplant recipients because they are given anti-rejection drugs. These drugs suppress the immune system to prevent the body from rejecting the donors stem cells. However, this low immunity also leaves the body more at risk for infection. This risk increases when more anti-rejection drugs are needed. Your treatment team will work with you to prevent and manage infections.

Graft-versus-host disease

People who have an ALLO transplant are also at risk of developing a post-transplant illness called graft-versus-host disease (GVHD). It occurs when the transplanted stem cells recognize the patients body as foreign and attack it, causing inflammation. GVHD ranges from mild to life-threatening. AUTO transplant recipients do not face this risk because the transplanted stem cells come from their own bodies.

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Side Effects of Stem Cell/Bone Marrow Transplantation ...

Repairing Chronic Muscle Tears with Stem Cells
Chronic muscle tears like hamstring pulls and shoulder rotator cuff muscles are tough to heal. Research suggests that injecting bone marrow stem cells into the area may solve that problem.

By: Chris Centeno

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Repairing Chronic Muscle Tears with Stem Cells - Video

What can mesenchymal stem cells do?

Mesenchymal stem cells (MSCs) are an example of tissue or 'adult' stem cells. They are multipotent, meaning they can produce more than one type of specialized cell of the body, but not all types. MSCs make the different specialized cells found in the skeletal tissues. For example, they can differentiate or specialize into cartilage cells (chondrocytes), bone cells (osteoblasts) and fat cells (adipocytes). These specialized cells each have their own characteristic shapes, structures and functions, and each belongs in a particular tissue.

Some early research suggested that MSCs might also differentiate into many different types of cells that do not belong to the skeletal tissues, such as nerve cells, heart muscle cells, liver cells and endothelial cells, which form the inner layer of blood vessels. These results have not been confirmed to date. In some cases, it appears that the MSCs fused together with existing specialized cells, leading to false conclusions about the ability of MSCs to produce certain cell types. In other cases, the results were an artificial effect caused by chemicals used to grow the cells in the lab.

Mesenchymal stem cell differentiation: MSCs can make fat, cartilage and bone cells. They have not been proven to make other types of cells of the body.

MSCs were originally found in the bone marrow. There have since been many claims that they also exist in a wide variety of other tissues, such as umbilical cord blood, adipose (fat) tissue and muscle. It has not yet been established whether the cells taken from these other tissues are really the same as, or similar to, the mesenchymal stem cells of the bone marrow.

The bone marrow contains many different types of cells. Among them are blood stem cells (also called hematopoietic stem cells; HSCs) and a variety of different types of cells belonging to a group called mesenchymal cells. Only about 0.001-0.01% of the cells in the bone marrow are mesenchymal stem cells.

It is fairly easy to obtain a mixture of different mesenchymal cell types from adult bone marrow for research. But isolating the tiny fraction of cells that are mesenchymal stem cells is more complicated. Some of the cells in the mixture may be able to form bone or fat tissues, for example, but still do not have all the properties of mesenchymal stem cells. The challenge is to identify and pick out the cells that can both self-renew (produce more of themselves) and can differentiate into three cell types bone, cartilage and fat. Scientists have not yet reached a consensus about the best way to do this.

No treatments using MSCs are yet available. However, several possibilities for their use in the clinic are currently being explored.

Bone and cartilage repair The ability of MSCs to differentiate into bone cells called osteoblasts has led to their use in early clinical trials investigating the safety of potential bone repair methods. These studies are looking at possible treatments for localized skeletal defects (damage at a particular place in the bone).

Other research is focussed on using MSCs to repair cartilage. Cartilage covers the ends of bones and allows one bone to slide over another at the joints. It can be damaged by a sudden injury like a fall, or over a long period by a condition like osteoarthritis, a very painful disease of the joints. Cartilage does not repair itself well after damage. The best treatment available for severe cartilage damage is surgery to replace the damaged joint with an artificial one. Because MSCs can differentiate into cartilage cells called chondrocytes, scientists hope MSCs could be injected into patients to repair and maintain the cartilage in their joints. Researchers are also investigating the possibility that transplanted MSCs may release substances that will tell the patients own cells to repair the damage.

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Mesenchymal stem cells: the 'other' bone marrow stem cells ...

Nichole Bushong shares her story of helping save someone elses live

J.O. PARKER joparker@registermedia.com

It was November 2013.

Nichole Bushong of Malcom received a phone call from the National Bone Marrow Donor Program.

She was a potential match for a bone marrow recipient, and the call came to ask if she would consider some initial blood tests to see if she might be a match.

Bushong, who owns Memories Maid in Grinnell, had signed on to the national registry in June 2013 after an uncles brother needed a transplant.

He ended up getting a transplant from another donor and is doing great now, recalled Bushong.

Bushong said some people on the registry wait years before receiving a call. In her case, it was just a few months.

Nichole Bushong is shown with her husband, Lucas, on their wedding day in August 2014. Bushong, along with Sam Coster, will be in Grinnell on Wednesday, April 22 to meet with local and area residents to talk about donating and signing up for the National Bone Marrow Registry. Courtesy Photo

A story of love

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Donating bone marrow was a piece of cake for Malcom woman

Next month Mr Brown and his wife will attend the wedding in the United States as very special guests.

He joined the Anthony Nolan register in the late 1980s when his baby son Michael - now 33 - was being treated for cancer.

A few years later, in 1991, he received a call to tell him that he was a match for a patient in the USA who was in desperate need of a transplant.

Mr Brown agreed to donate and travelled to the Harley Street Clinic in London to make the lifesaving donation.

He gave his bone marrow on the morning of May 17, 1991, and it was immediately picked up by a courier who flew over to the USA on Concorde, on a journey of more than 3,500 miles, which allowed the patient to have his transplant that evening.

Mr Brown said: It was so rewarding after making the donation, I went round with a huge smile on my face for six months.

Following the donation, the sales manager learned that his bone marrow had gone to a 44-year-old man called Rick Haines who lived in Delaware and who was suffering from aplastic anaemia.

Afterwards, Mr Haines, an engineer in the motor industry, contacted Mr Brown to thank him.

Mr Haines, now 68, explained that he had feared he would not live to see his young daughter walk down the aisle, and a deal was struck.

Donor organs from cancer patients should be transplanted despite risks

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Bone marrow donation ends in a wedding promise

Stem Cell Research in Cardiology
Bharat Book Bureau provides the report, on Stem Cell Research in Cardiology. The study is segmented by Source (Allogenic and Autogenic) and by Type (Bone Marrow Stem Cells, Embryonic...

By: Bharat Book

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Stem Cell Research in Cardiology - Video

Telomeres are short stretches of repeated nucleotides that protect the ends of chromosomes. In somatic cells, these protective sequences become shorter with each cellular replication until a critical length is reached, which can trigger cell death.

In actively replicating cells such as germ cells, embryonic stem cells, and blood stem cells of the bone marrow, the enzyme telomerase replenishes these protective caps to ensure adequate replication. Cancer cells also seem to have the ability to activate telomerase, which allows them to keep dividing indefinitely, with dire consequences for the patient. However, according to a study published April 10 in the JNCI: Journal of the National Cancer Institute, the extent to which cancer cells can utilize telomerase may depend on which variants of the genes related to telomerase activity are expressed in an individual's cells.

Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle. Thus, a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow the presumably causal association of telomere length and cancer mortality to be studied.

To perform this analysis, Line Rode, M.D., Ph.D., of the Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, and colleagues, used data from two prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 64,637 individuals followed from 1991-2011. Participants completed a questionnaire and had a physical examination and blood drawn for biochemistry, genotyping, and telomere length assays.

For each subject, the authors had information on physical characteristics such as body mass index, blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables. In addition to the measure of telomere length for each subject, three single nucleotide polymorphisms of TERC, TERT, and OBFC1 were used to construct a score for the presence of telomere shortening alleles.

A total of 7607 individuals died during the study, 2420 of cancer. Overall, as expected, decreasing telomere length as measured in leukocytes was associated with age and other variables such as BMI and smoking and with death from all causes, including cancer. Surprisingly, and in contrast, a higher genetic score for telomere shortening was associated specifically with decreased cancer mortality, but not with any other causes of death, suggesting that the slightly shorter telomeres in the cancer patients with the higher genetic score for telomere shortening might be beneficial because the uncontrolled cancer cell replication that leads to tumor progression and death is reduced.

The authors conclude, "We speculate that long telomeres may represent a survival advantage for cancer cells, allowing multiple cell divisions leading to high cancer mortality."

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Contact info:

Stig E. Bojesen, M.D., D.M.Sc., stig.egil.bojesen@regionh.dk

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Telomeres and cancer mortality: The long and the short of it

Frederick, MD (PRWEB) April 09, 2015

Based upon strong market demand, RoosterBio Inc has announced the commercial launch of RoosterVial-hBM-50M MSC, a single vial containing 50 million human bone-marrow derived mesenchymal stem/stromal cells. This unprecedented, ultra-high cell number product configuration enables Regenerative Medicine organizations to accelerate scale-up and product development activities. RoosterBios core technology, which includes cell and media systems, allows tissue engineers, biofabricators, 3D bioprinters and cell therapy developers to instantly scale up, using simplified and standardized methods.

The 50 million hMSC vial delivers immediate cell biomass without the need for prior expansion. This results in saving significant time, resources and expense during bioprocess scale-up optimization. Since the system contains the most well-characterized hMSCs available on the market, the industry is assured robust and reproducible results. As with other RoosterBio products, this 50 million cell product is capable of greater than 100-fold expansion (>5 billion cells) within two weeks when cultured in RoosterBio medium. Prior to this technology, obtaining such cell numbers so rapidly was virtually impossible.

RoosterBio continues to broaden their portfolio of product formats, providing solutions for an extensive range of Regenerative Medicine therapeutic categories. The evolving product portfolio enables researchers and product developers to perform small scale screening studies, large scale development studies, and now, scale-up manufacturing bioprocess experiments using the 50 million cell product. Rapid prototyping of 3D bioprinted tissues utilizing hMSCs as the primary component of the cellular bioink is also now achievable. The Company offers various product configurations including 1 million cell vials, 10 million cell vials, and high performance media systems, as well as pre-assembled working cell banks and kits for rapidly achieving stem cell biomass. Jon Rowley, CEO of RoosterBio stated: "The Industry has published a technology roadmap for scalable cell manufacturing and 3D bioprinting, yet the materials needed to test and implement these technologies are not readily available. RoosterBio is addressing this major roadblock with innovative product formats that enable users to do more work, faster, and with much less out-of-pocket expense."

RoosterBios mission is to accelerate the development and commercialization of Regenerative Medicine products, by providing standardized stem cell product platforms that enable rapid translation of discoveries into product development. For more information, please email Priya Baraniak at priya@roosterbio.com or phone 1-412-606-1160.

About RoosterBio

RoosterBio is a privately held biofabrication tools company focused on accelerating the development of a sustainable regenerative medicine industry, one customer at a time. RoosterBios products are high volume, affordable, and well-characterized adult human mesenchymal stem/stromal cells (hMSCs) paired with highly engineered media systems. RoosterBio has simplified and standardized how stem cells are purchased, expanded, and used in development, leading to marked time and costs savings for customers. RoosterBios innovative products are ushering in a new era of productivity and standardization into the field, where researchers spend newly found time and money performing more high-value experiments, accelerating the road to discovery in Regenerative Medicine. For more information on RoosterBio and adult stem cells, you can visit http://www.roosterbio.com, follow on twitter (@RoosterBio), or read the highly-acclaimed blog Democratizing Cell Technologies (http://www.roosterbio.blogspot.com).

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RoosterBio Inc. launches new stem cell product format enabling rapid, scalable cell manufacturing and 3D bioprinting

Rice University and Texas Children's Hospital scientists are using stem cells from amniotic fluid to promote the growth of robust, functional blood vessels in healing hydrogels.

In new experiments, the lab of bioengineer Jeffrey Jacot combined versatile amniotic stem cells with injectable hydrogels used as scaffolds in regenerative medicine and proved they enhance the development of vessels needed to bring blood to new tissue and carry waste products away.

The results appear in the Journal of Biomedical Materials Research Part A.

Jacot and his colleagues study the use of amniotic fluid cells from pregnant women to help heal infants born with congenital heart defects. Such fluids, drawn during standard tests, are generally discarded but show promise for implants made from a baby's own genetically matched material.

He contends amniotic stem cells are valuable for their ability to differentiate into many other types of cells, including endothelial cells that form blood vessels.

"The main thing we've figured out is how to get a vascularized device: laboratory-grown tissue that is made entirely from amniotic fluid cells," Jacot said. "We showed it's possible to use only cells derived from amniotic fluid."

In the lab, researchers from Rice, Texas Children's Hospital and Baylor College of Medicine combined amniotic fluid stem cells with a hydrogel made from polyethylene glycol and fibrin. Fibrin is a biopolymer critical to blood clotting, cellular-matrix interactions, wound healing and angiogenesis, the process by which new vessels branch off from existing ones. Fibrin is widely used as a bioscaffold but suffers from low mechanical stiffness and rapid degradation. Combining fibrin and polyethylene glycol made the hydrogel much more robust, Jacot said.

The lab used vascular endothelial growth factor to prompt stem cells to turn into endothelial cells, while the presence of fibrin encouraged the infiltration of native vasculature from neighboring tissue.

Mice injected with fibrin-only hydrogels showed the development of thin fibril structures, while those infused with the amniotic cell/fibrin hydrogel showed far more robust vasculature, according to the researchers.

Similar experiments using hydrogel seeded with bone marrow-derived mesenchymal cells also showed vascular growth, but without the guarantee of a tissue match, Jacot said. Seeding with endothelial cells didn't work as well as the researchers expected, he said.

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Amniotic stem cells demonstrate healing potential

Miami, FL (PRWEB) April 09, 2015

Global Stem Cells Group subsidiary Adimarket has been named the Latin America distributor for bone marrow technology leader Ranfac Corporation. The announcement coincides with Global Stem Cells Groups most recent expansion plans in Latin America, an ongoing effort to meet the regions growing demands for access to regenerative medicine and stem cell therapies.

Ranfac manufactures state-of-the-art surgical, radiology, hematology and orthopedic products including a range of bone marrow aspiration needles, each designed to provide a simple means of harvesting marrow from the patients sternum (breastbone) or the iliac crest (part of the pelvic bone) for a variety of medical procedures. Ranfacs newest technology is designed to harvest high quality bone marrow derived cells without the need for centrifugation.

Ranfac bone marrow technology is used by physicians and medical specialists worldwide. Global Stem Cells Group Advisory Board member Joseph Purita, M.D., a pioneer in the use of laser and stem cell therapies in orthopedic medicine, endorses Ranfacs bone marrow aspiration technology. Purita recently joined other specialists including fellow GSCG Advisory Board member David B Harrell, PhD, Brt, OF, FAARM, FRIPH, DABRM, in a trial study and white paper collaboration on Ranfacs new, non-centrifugal bone marrow technology.

Both Purita and Harrell endorse the Ranfac systems enhanced safety and ability to increase the concentrations of stem and progenitor cells during the bone marrow aspiration process.

Our ground-breaking hematology and orthopedic products for bone marrow access, aspiration, stem cell harvesting and biopsy procedures are designed to provide a more efficient result during critical procedures, says Ranfac CEO Barry Zimble. We believe that this is the perfect time to team with Global Stem Cells Group as our distribution partner in Latin Americas fast-growing medical community.

The collaboration between Global Stem Cells Group and Ranfac is another step toward GSCGs commitment to expanding its presence in communities that need and deserve access to cutting-edge regenerative medicine, not only in Latin America but also worldwide.

The timing couldnt be better to represent Ranfacs cutting edge bone marrow technology in the emerging markets of Latin America. Global is always looking to provide patients and practitioners with the best resources that regenerative medicine has to offer says Ricardo DeCubas, Global Stem Cells Group co-founder and Regenestem CEO.

For more information visit the Global Stem Cells Group website, email bnovas@stemcellsgroup.com, or call 305-224-1858.

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Global Stem Cells Group Subsidiary Adimarket Named Latin American Distributor for Ranfac Bone Marrow Technology