Monkeys show reduced Parkinsonian symptoms following a donor-matched iPS cell-based therapy. Misaki Ouchida, Center for iPS Cell Research and Application, Kyoto University

One of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys. In its latest study, the Jun Takahashi lab shows monkeys with Parkinson's disease symptoms show significant improvement over two years after being transplanted neurons prepared from human iPS cells. The study, which can be read in Nature, is expected to be a final step before the first iPS cell-based therapy for a neurodegenerative disease.

Parkinson's disease degenerates a specific type of cells in the brain known as dopaminergic (DA) neurons. It has been reported that when symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin, which is why Professor Takahashi, who is also a neurosurgeon specializing in Parkinson's disease, plans to use DA neurons made from iPS cells to treat patients.

"Our research has shown that DA neurons made from iPS cells are just as good as DA neurons made from fetal midbrain. Because iPS cells are easy to obtain, we can standardize them to only use the best iPS cells for therapy, " he said.

To test the safety and effectiveness of DA neurons made from human iPS cells, Tetsuhiro Kikuchi, a neurosurgeon working in the Takahashi lab, transplanted the cells into the brains of monkeys.

"We made DA neurons from different iPS cells lines. Some were made with iPS cells from healthy donors. Others were made from Parkinson's disease patients," said Kikuchi, who added that the differentiation method used to convert iPS cells into neurons is suitable for clinical trials.

It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survived, but Kikuchi found this was not the case. More important than the number of cells was the quality of the cells.

"Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival," Kikuchi said.

To understand why, he looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors. One of those genes was Dlk1.

"Dlk1 is one of the predictive markers of cell quality for DA neurons made from embryonic stem cells and transplanted into rat. We found Dlk1 in DA neurons transplanted into monkey. We are investigating Dlk1 to evaluate the quality of the cells for clinical applications."

Another feature of the study that is expected to extend to clinical study is the method used to evaluate cell survival in the host brains. The study demonstrated that magnetic resonance imaging (MRI) and position electron tomography (PET) are options for evaluating the patient post surgery.

"MRI and PET are non-invasive imaging modalities. Following cell transplantation, we must regularly observe the patient. A non-invasive method is preferred," said Takahashi.

The group is hopeful that it can begin recruiting patients for this iPS cell-based therapy before the end of next year. "This study is our answer to bring iPS cells to clinical settings," said Takahashi.

This article has been republished frommaterialsprovided byCIRA, Kyoto University. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Monkeys With Parkinson's Disease Successfully Treated With Human Stem Cell Transplants - Technology Networks

IPS Cell Therapy Comments Off on Monkeys With Parkinson’s Disease Successfully Treated With Human Stem Cell Transplants – Technology Networks | September 1st, 2017

Tippi MacKenzie, MD, a pediatric and fetal surgeon at UCSF Benioff Childrens Hospital San Francisco, is the principal investigator for a clinical trial that will use in utero stem cell transplants to treat fetuses with an inherited disorder that restricts the bloods ability to carry oxygen to vital organs. Credit: Cindy Chew

UCSF Benioff Children's Hospitals in San Francisco and Oakland will pioneer stem cell transplants for a uniquely challenging patient population: second-trimester fetuses stricken with a potentially fatal disease.

The two hospitals are enrolling 10 pregnant women in the first phase of a clinical trial to treat fetuses with an inherited disorder that restricts the blood's ability to carry oxygen to vital organs. The trial, the first of its kind in the world, is funded by a $12.1 million grant from the California Institute for Regenerative Medicine.

Alpha thalassemia (ATM) affects 5 percent of the world's population, but is significantly more prevalent in China, Southeast Asia, India and the Middle East parts of the globe where many residents of the San Francisco Bay Area claim their origins. In its most extreme form, alpha thalassemia major (ATM), the condition leads to progressive anemia and heart failure before birth. Standard treatment in the United States includes lifelong blood transfusions.

Stem cell transplants from a matched donor in childhood have proven to be curative in some cases, but patients face risks, including graft-versus-host disease and serious side effects from immune-suppression drugs.

The trial is based on the premise that risks could be minimized by harnessing the "tolerance" between the pregnant woman and fetus before birth, said principal investigator Tippi MacKenzie, MD, a pediatric and fetal surgeon at UCSF Benioff Children's Hospital San Francisco.

Hope That Procedure Could Be Adopted Worldwide

"In performing the procedure in utero when the fetus's immune system is underdeveloped, we can avoid the aggressive treatments required for postnatal transplants for children with alpha thalassemia," MacKenzie said. "Eventually, the procedure may become a treatment option in parts of the world where ATM is most common. Due to lack of treatment possibilities in many countries, most pregnancies are either terminated on diagnosis or result in fetal demise," she said.

The trial follows a decades-long odyssey marked by triumphs and tribulations for researchers in the field. Fetal transplants using stem cells from other fetuses to treat blood disorders were carried out in the 1980s, but were only marginally successful due to engraftment failure. Researchers around the world searched for answers by turning to animal studies.

'Eureka Moment' Spurred Sea Change

"The fetus, unlike a fully developed human, can accept foreign cells, because its immune system is not yet primed to fight bacteria and viruses," said MacKenzie. "This undeveloped immune system benefits the fetus throughout the pregnancy, because it prevents it from launching an immune response to its mother's cells that are naturally circulating in its bloodstream."

Further research led to Mackenzie's "eureka moment," when it was discovered that the mother's immune system is actually responsible for rejecting other cells that are transplanted into the fetus. If the mother's cells are transplanted, they can engraft without being rejected. "This led to a sea change in our strategy to use maternal cells for the transplants," she said.

In the trial, bone marrow will be collected from women who are between 18 and 25 weeks pregnant, with a fetal diagnosis of ATM. The bone marrow cells will be processed and hematopoietic cells immature stem cells that can evolve into all types of blood cells will be singled out from the mix. They will then be injected through the woman's abdomen, into the umbilical vein of the fetus, where they can circulate through the bloodstream, developing into healthy mature blood cells.

The procedure is not without risks to the fetus and the pregnant woman. To minimize risks, the researchers restricted the trial to ATM, since the fetus is already undergoing blood transfusions. "An additional procedure for the transplantation is not necessary, since the maternal stem cells are infused at the same time as an in utero blood transfusion," said Elliott Vichinsky, MD, director of hematology/oncology at UCSF Benioff Children's Hospital Oakland, who will head the hematologic management of the fetus and newborn. "This should reduce additional risks to the fetus." Since the underlying disease causes complications, the woman will be monitored throughout her pregnancy and the fetus will continue to receive blood transfusions until birth.

UCSF is a pioneer in thalassemia research and the birthplace of fetal surgery. UCSF Benioff Children's Hospital Oakland is home to the Northern California Comprehensive Thalassemia Center, which was established in 1991 and is now the largest such program nationwide, with a focus on caring for patients and leading research into new treatments.

"We are excited about launching this trial, which combines the expertise of UCSF Benioff Children's Hospitals in San Francisco and Oakland. This study offers families with a usually fatal ATM pregnancy the chance of survival and cure," said Vichinsky, who founded the Northern California Comprehensive Thalassemia Center.

Treatment May Be Tested for Sickle Cell Anemia

Patient recruitment will continue for five years, during which pregnant women and their babies will be followed after birth for 30 days and one year respectively. If successful, the procedure will be carried out for fetuses with beta thalassemia, a more common and less serious variant of the disorder, as well as sickle cell anemia, in collaboration with Children's Hospital of Philadelphia. Other conditions requiring stem cell transplants after birth may be considered, said MacKenzie.

The incidence of ATM is unknown because most fetuses with the disorder die before delivery. The condition occurs when both parents are carriers for thalassemia. In places where women have access to prenatal care, ATM is usually suspected on ultrasound and confirmed by DNA analysis in the second trimester.

Explore further: Immune system drives pregnancy complications after fetal surgery in mice

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In utero stem cell transplants may replace riskier childhood transplants for multiple conditions - Medical Xpress

Bone Marrow Stem Cells Comments Off on In utero stem cell transplants may replace riskier childhood transplants for multiple conditions – Medical Xpress | August 31st, 2017

AsianScientist (Aug. 30, 2017) - In a study published in Cell Stem Cell, scientists in Japan and Switzerland have found that bacterial infections can stress blood-producing stem cells in the bone marrow and reduce their ability to self-replicate.

When a person becomes infected with a virus or bacteria, immune cells in the blood or lymph react to the infection. Some of these immune cells use sensors on their surfaces, called Toll-like receptors (TLR), to distinguish invading pathogens from molecules that are expressed by the host. By doing so, they can attack and ultimately destroy pathogens thereby protecting the body without attacking host cells.

Bone marrow contains hematopoietic stem cells which create blood cells, such as lymphocytes and erythrocytes, throughout the lifetime of an individual. When infection occurs, a large number of immune cells are activated and consumed. Hence, it is necessary to replenish these immune cells by increasing blood production in bone marrow.

Recent studies have revealed that immune cells are not the only cells that detect the danger signals associated with infection. Hematopoietic stem cells also identify these signals and use them to adjust blood production. However, little was known about how hematopoietic stem cells respond to bacterial infection or how it affected their function.

In this study, researchers from Kumamoto University and the University of Zurich analyzed the role of TLRs in hematopoietic stem cells upon bacterial infection, given that both immune cells and hematopoietic stem cells have TLRs.

To generate a model of bacterial infection, researchers injected one of the key molecules found in the outer membrane of gram negative bacteria and known to cause sepsislipopolysaccharide (LPS)into lab mice. They then analyzed the detailed role of TLRs in hematopoietic stem cell regulation by combining genetically modified animals that do not have TLR and related molecules, or agents that inhibit these molecules.

The results showed that LPS spread throughout the body, with some eventually reaching the bone marrow. This stimulated the TLRs of the hematopoietic stem cells and induced them to proliferate. They also discovered that while LPS promoted stem cell proliferation, it also induced stressed the stem cells, impairing their ability to successfully self-replicate and resulting in diminished blood production. Similar results were obtained after infection with Escherichia coli bacteria.

Fortunately we were able to confirm that this molecular reaction can be inhibited by drugs, said Professor Hitoshi Takizawa of Kumamoto University who led the study. The medication maintains the production of blood and immune cells without weakening the immune reaction against pathogenic bacteria. It might be possible to simultaneously prevent blood diseases and many bacterial infections in the future.

The article can be found at: Takizawa et al. (2017) Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.

Source: Kumamoto University.Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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Bacterial Infection Stresses Blood Stem Cells - Asian Scientist Magazine

Bone Marrow Stem Cells Comments Off on Bacterial Infection Stresses Blood Stem Cells – Asian Scientist Magazine | August 31st, 2017

B. Bick, . Poindexter, UT Med. School/SPL

A depletion of brain cells that produce dopamine is responsible for the mobility problems seen in people with Parkinsons disease.

Japanese researchers report promising results from an experimental therapy for Parkinsons disease that involves implanting neurons made from reprogrammed stem cells into the brain. A trial conducted in monkeys with a version of the disease showed that the treatment improved their symptoms and seemed to be safe, according to a report published on 30 August in Nature1.

The studys key finding that the implanted cells survived in the brain for at least two years without causing any dangerous effects in the body provides a major boost to researchers hopes of testing stem-cell treatments for Parkinsons in humans, say scientists.

Jun Takahashi, a stem-cell scientist at Kyoto University in Japan who led the study, says that his team plans to begin transplanting neurons made from induced pluripotent stem (iPS) cells into people with Parkinsons in clinical trials soon.

The research is also likely to inform several other groups worldwide that are testing different approaches to treating Parkinsons using stem cells, with trials also slated to begin soon.

Nature breaks down the latest research and what it means for the future of stem-cell treatments.

Parkinsons is a neurodegenerative condition caused by the death of cells called dopaminergic neurons, which make a neurotransmitter called dopamine in certain areas of the brain. Because dopamine-producing brain cells are involved in movement, people with the condition experience characteristic tremors and stiff muscles. Current treatments address symptoms of the disease but not the underlying cause.

Researchers have pursued the idea that pluripotent stem cells, which can form any cell type in the body, could replace dead dopamine-making neurons in people with Parkinsons, and thus potentially halt or even reverse disease progression. Embryonic stem cells, derived from human embryos, have this capacity, but they have been the subject of ethical debates. Induced pluripotent stem (iPS) cells, which are made by coaxing adult cells into an emybronic-like state, have the same versatility without the associated ethical concerns.

Takahashis team transformed iPS cells derived from both healthy people and those with Parkinsons into dopamine-producing neurons. They then transplanted these cells into macaque monkeys with a form of the disease induced by a neuron-killing toxin.

The transplanted brain cells survived for at least two years and formed connections with the monkeys brain cells, potentially explaining why the monkeys treated with cells began moving around their cages more frequently.

Crucially, Takahashis team found no sign that the transplanted cells had developed into tumours a key concern with treatments that involve pluripotent cells or that they evoked an immune response that couldnt be controlled with immune-suppressing drugs.

Its addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans, says Anders Bjorklund, a neuroscientist at Lund University in Sweden.

I hope we can begin a clinical trial by the end of next year, says Takahashi. Such a trial would be the first iPS cell trial for Parkinson's. In 2014, a Japanese woman in her 70s became the first person to receive cells derived from iPS cells, to treat her macular degeneration.

In theory, iPS cells could be tailor-made for individual patients, which would eliminate the need to use drugs that suppress a possible immune response to foreign tissues.

But customized iPS cells are expensive to make and can take a couple months to derive and grow, Takahashi notes. So his team instead plans to establish iPS cell lines from healthy people and then use immune cell biomarkers to match them to people with Parkinsons in the hope of minimizing the immune response (and therefore the need for drugs to blunt the attack).

In a study described in an accompanying paper in Nature Communications2, Takahashis team implanted into monkeys iPS-cell-derived neurons from different macaques. They found that transplants between monkeys carrying similar white blood cell markers triggered a muted immune reaction.

Earlier this year, Chinese researchers began a Parkinsons trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.

Meanwhile, researchers who are part of a Parkinsons stem-cell therapy consortium called GForce-PD, of which Takahashis team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment, notes Bjorklund, also a consortium member.

Jeanne Loring, a stem-cell scientist at the Scripps Research Institute in La Jolla, California, favours transplanting iPS-derived neurons made from a patients own cells. Although expensive, this approach avoids dangerous immunosuppressive drugs, she says. And because iPS cells are established anew for each patient, the lines go through relatively few cell divisions, minimizing the risk that they will develop tumour-causing mutations. Loring hopes to begin her teams trial in 2019. This shouldnt be a race and were cheering for success by all, she says.

Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City who is working on a trial that will use neurons made from embryonic stem cells, says that there are still issues to work out, such as the number of cells needed in each transplant procedure. But he says that the latest study is a sign that we are ready to move forward.

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Reprogrammed cells relieve Parkinson's symptoms in trials - Nature.com

IPS Cell Therapy Comments Off on Reprogrammed cells relieve Parkinson’s symptoms in trials – Nature.com | August 31st, 2017

On Monday, the U.S. Food and Drug Administration (FDA) announced that the agency is targeting clinics that offer unproven stem cell therapies, calling such offices "unscrupulous clinics" selling "so-called cures." The FDA seized materials from one clinic in California, and sent a warning letter to another in Florida.

The FDA will not allow deceitful actors to take advantage of vulnerable patients by purporting to have treatments or cures for serious diseases without any proof that they actually work," said FDA Commissioner Dr. Scott Gottlieb in a statement.

The agency announced that on Friday, Aug. 25th, U.S. Marshals seized five vials of a vaccine that is intended for people at a high risk for smallpox (for example, people in the military) from StemImmune Inc. in San Diego, California. The FDA says it learned that StemImmune was using the vaccines as well as stem cells from body fat to create an unapproved stem cell therapy. On its website, StemImmune says "The patients own (autologous, adult) stem cells, armed with potent anti-cancer payloads, function like a Trojan Horse, homing to tumors and cancer cells, undetected by the immune system." The stem cell treatment was injected into the tumors of cancer patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California.

MORE: Three People Are Nearly Blind After Getting a Stem Cell Treatment

The FDA also sent a warning later to U.S. Stem Cell Clinic in Sunrise, Florida. The company recently came under public scrutiny when a March report revealed that three people had severe damage to their vision one woman went blindafter they were given shots of what the company said were stem cells into their eyes during a study sponsored by the clinic. The FDA says that an inspection of U.S. Stem Cell Clinic revealed that the clinic was using stem cells to treat diseases like Parkinson's, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis. According to the FDA, there are currently only a limited number of stem cell therapies approved by the agencyincluding ones involving bone marrow, for bone marrow transplants in cancer care, and cord blood for specific blood-related disorders. There are no approved stem cell treatments for other diseases.

The FDA says U.S. Stem Cell Clinic also attempted to interfere with the FDA's most recent inspection by refusing to allow FDA investigators to enter without an appointment, and denied the agency access to its employees. "Refusing to permit entry or FDA inspection is a violation of federal law," the FDA says.

Action by the FDA on clinics promoting unproven stem cell therapies is "a long time coming," says Sean Morrison, former president of the International Society for Stem Cell Research (ISSCR) and d irector of the Childrens Research Institute at UT Southwestern. "C linics are preying on the hopes of desperate patients claiming they can cure all manner of diseases with stem cells that have not been tested in clinical trials, and in some cases, are flat out impossible."

In the past, medical experts were concerned over Americans traveling to countries with less medical regulation for stem cell therapies, but Morrison says such clinics have been popping up stateside over the last five years. "It's not a few companies in the U.S. making claims about therapies with stem cells," says Morrison. "It's scores of companies. The problem has exploded in the U.S."

Morrison blames the lack of FDA crackdown in the past for the growing problem. "At some point people made the calculation that the FDA didnt seem to be enforcing these laws," he says. "The margins are huge. They charge people tens of thousands of dollars."

Since stem cell therapy is still an active and legitimate area of scientific research, it can be hard for Americans to figure out what is safe and effective and what is not. Even when it comes to clinical trials, the scientific soundness is murky. A July 2017 paper reported that 18 U.S. companies have registered "patient-sponsored" stem cell studies on ClinicalTrials.gov. That means that the patients receiving the treatment paid for them, which isn't the case in more legitimate studies. None of these were gold standard studies: meaning the people were not randomly assigned to receive the treatment or not, so the participants knew they were receiving the therapy that could bias the results. Only seven of the studies disclosed upfront that patients had to pay to join the study, and none revealed that the costs ranged from $5,000 to $15,000 a treatment, Wired reports.

While Morrison says he's glad the FDA has taken action, he says it's not enoughat least not yet. "The FDA has to show that there is really a sustained commitment to enforcement," he says. "When the FDA wasnt bringing actions against these companies, I think people thought this meant that it was a gray area and that they could get away with it."

Undoing that damage could be a long process, and one that Morrison says needs consistent attention by the agency. In a letter released on Monday, FDA commissioner Gottlieb said the agency is stepping up enforcement of stem cell therapies and regenerative medicine. "Ive directed the FDA to launch a new working group to pursue unscrupulous clinics through whatever legally enforceable means are necessary to protect the public health," said Gottlieb. Whether those efforts have an impact remains to be seen.

Excerpt from:
FDA Cracks Down on Stem Cell Clinics But Patients Are Still at Risk - TIME

Bone Marrow Stem Cells Comments Off on FDA Cracks Down on Stem Cell Clinics But Patients Are Still at Risk – TIME | August 30th, 2017

Biol Res 45: 279-287, 2012

RESEARCH ARTICLES

In Osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis

Ana Mara Pino1, Clifford J. Rosen2 and J. Pablo Rodrguez1*

1Laboratorio de Biologa Celular y Molecular, INTA, Universidad de Chile, 2Maine Medical Center Research Institute, Scarborough, Maine, USA.

ABSTRACT

The formation, maintenance, and repair of bone tissue involve close interlinks between two stem cell types housed in the bone marrow: the hematologic stem cell originating osteoclasts and mesenchymal stromal cells (MSCs) generating osteoblasts. In this review, we consider malfunctioning of MSCs as essential for osteoporosis. In osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis and insufficient osteoblastogenesis.

MSCs are the common precursors for both osteoblasts and adipocytes, among other cell types. MSCs' commitment towards either the osteoblast or adipocyte lineages depends on suitable regulatory factors activating lineage-specific transcriptional regulators. In osteoporosis, the reciprocal balance between the two differentiation pathways is altered, facilitating adipose accretion in bone marrow at the expense of osteoblast formation; suggesting that under this condition MSCs activity and their microenvironment may be disturbed. We summarize research on the properties of MSCs isolated from the bone marrow of control and osteoporotic post-menopausal women. Our observations indicate that intrinsic properties of MSCs are disturbed in osteoporosis. Moreover, we found that the regulatory conditions in the bone marrow fluid of control and osteoporotic patients are significantly different. These conclusions should be relevant for the use of MSCs in therapeutic applications.

Key words: MSCs, osteoporosis, adipogenesis, bone marrow microenvironment

BACKGROUND

The formation, maintenance, and repair of bone tissue depend on fine-tuned interlinks in the activities of cells derived from two stem cell types housed in the bone marrow interstice. A hematologic stem cell originates osteoclasts, whereas osteoblasts derive from mesenchymal stem cells (MSCs). Bone tissue is engaged in an unceasing process of remodelling through the turnover and replacement of the matrix: while osteoblasts deposit new bone matrix, osteoclasts degrade the old one.

Bone marrow provides an environment for maintaining bone homeostasis. The functional relationship among the different cells found in bone marrow generates a distinctive microenvironment via locally produced soluble factors, the extracellular matrix components, and systemic factors (Raisz, 2005; Sambrook and Cooper, 2006), allowing for autocrine, paracrine and endocrine activities. If only the main cellular components of the marrow stroma are considered, the activity of adipocytes, macrophages, fibroblasts, hematopoietic, endothelial and mesenchymal stem cells and their progeny bring about a complex range of signals.

Osteoporosis is a bone disease characterized by both decreased bone quality and mineral density. In postmenopausal osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis, inadequate osteoblastogenesis and altered bone microarchitecture.

The pathogenesis of the disease is hitherto unknown, hence the interest in basic and clinical research on the mechanisms involved (Raisz, 2005; Sambrook and Cooper, 2006). Cell studies on the origin of postmenopausal osteoporosis initially focused on osteoclastic activity and bone resorption processes; then on osteoblastogenesis, and more recently on the differentiation potential of mesenchymal stem cells (MSCs) (Shoback, 2007). Moreover, distinctive environmental bone marrow conditions appear to provide support for the development and maintenance of unbalanced bone formation and resorption (Nuttall and Gimble, 2004; Tontonoz et al., 1994). In this review, we consider the participation of the differentiation potential of MSCs, the activity of bone marrow adipocytes and the generation of a distinctive bone marrow microenvironment.

MESENCHYMAL STEM CELLS (MSCs)

Bone marrow contains stem-like cells that are precursors of nonhematopoietic tissues. These cells were initially referred to as plastic-adherent cells or colony forming-unit fibroblasts and subsequently as either mesenchymal stem cells or marrow stromal cells (MSCs) (Minguell et al., 2001; Lindnera et al., 2010; Kolf et al., 2007). There is much interest in these cells because of their ability to serve as a feeder layer for the growth of hematopoietic stem cells, their multipotentiality for differentiation, and their possible use for both cell and gene therapy (Minguell et al., 2001; Kolf et al., 2007). Friedenstein et al. (1970) initially isolated MSCs by their adherence to tissue culture surfaces, and essentially the same protocol has been used by other investigators. The isolated cells were shown to be multipotential in their ability to differentiate in culture or after implantation in vivo, giving rise to osteoblasts, chondrocytes, adipocytes, and/or myocytes.

MSCs populations in the bone marrow or those that are isolated and maintained in culture are not homogenous, but rather consist of a mixture of uncommitted, partially committed and committed progenitors exhibiting divergent stemness (Baksh et al., 2004). These heterogeneous precursor cells are morphologically similar to the multipotent mesenchymal stem cells, but differ in their gene transcription range (Baksh et al., 2004). It has been proposed that in such populations, cell proliferation, differentiation and maturation are in principle independent; stem cells divide without maturation, while cells close to functional competence may mature, but do not divide (Song et al., 2006).

Several molecular markers identify committed progenitors and the end-stage phenotypes, but at present there are no reliable cell markers to identify the uncommitted mesenchymal stem cells. Given the difficulty to identify a single marker to evaluate the population of stem cells, various combinations of these markers may be used (Seo et al., 2004; Lin et al., 2008; Xu et al., 2009). Therefore, MSCs are mainly defined in terms of their functional capabilities: self-renewal, multipotential differentiation and transdifferentiation (Baksh et al., 2004).

Hypothetically, the fate of MSCs appears to be determined during very early stages of cell differentiation ("commitment"). During this mostly unknown period, both intrinsic (genetic) and environmental (local and/or systemic) conditions interplay to outline the cell's fate towards one of the possible lineages. Based on microarray assays comparing gene expression at the stem state and throughout differentiation, it has been proposed that MSCs multilineage differentiation involves a selective mode of gene expression (Baksh et al., 2004; Song et al., 2006). It appears that "stemness" is characterized by promiscuous gene expression, where pluripotential differentiation results from the maintenance of thousands of genes at their intermediate expression levels. Upon commitment to one fate, only the few genes that are needed for differentiation towards the target tissue are selected for continuous expression, while the rest are downregulated (Zipori, 2005; Zipori, 2006).

The gene expression profile of undifferentiated human MSCs (h-MSCs) show high expression of several genes (Song et al., 2006; Tremain et al., 2001), but the contribution of such genes in preserving h-MSC properties, such as self-renewal and multilineage differentiation potential, or in regulating essential signalling pathways is largely unknown (Song et al., 2006). Several factors like age (Zhou et al., 2008), culture condition (Kultere et al., 2007), microenvironment (Kuhn and Tuan, 2010), mechanical strain (McBride et al., 2008) and some pathologies (Seebach et al., 2007; Hofer et al., 2010) appear to affect MSCs' intrinsic activity.

MSCs' commitment towards either the osteoblast or adipocyte lineage is determined by a combination of regulatory factors in the cells' microenvironment. The adequate combination leads to the activation of lineage-specific transcriptional regulators, including Runx2, Dlx5, and osterix for osteoblasts, and PPARy2 and a family of CAAT enhancer binding proteins for adipocytes (Murunganandan et al., 2009). Although the appropriate collection of regulatory factors required for suitable differentiation of MSCs is largely unknown, the TGF/BMPs, Wnt and IGF-I signals are briefly considered.

Several components of the BMP family are secreted in the MSCs' microenvironment (Lou et al., 1999, Gori et al., 1999; Gimble et al., 1995); BMP-2/4/6/7 have been identified as mediators for MSCs differentiation into osteoblasts or adipocytes (Muruganadan et al., 2009). The intracellular effects of BMPs are mediated by an interaction with cell surface BMP receptors (BMPRs type I and type II) (Gimble et al., 1995). It seems that differentiation into adipocytes or osteoblasts is highly dependent on the type of receptor I expressed by the cells, so that adipogenic differentiation requires signaling through BMPR IA, while osteogenic differentiation is dependent on BMPR IB activation (Gimble et al., 1995). The active receptors trigger the activation of Smad proteins, which induce specific genes. Under osteogenic differentiation, BMP action promotes osterix formation through Runx2-dependent and Runx2-independent pathways, thereby triggering osteogenic differentiation (Gori et al., 1999; Shapiro, 1999).

In addition to the role of BMPs in bone formation, BMPs also positively mediate the adipogenic differentiation pathways (Haiyan et al., 2009). It has been demonstrated that there is a binding site for Smad proteins in the promoter region of PPARy2 (Lecka-Czernik et al., 1999), and over-expression of Smad2 protein suppresses the expression of Runx2 (Li et al., 1998). These observations suggest that adequate content of osteoblasts and adipocytes in the bone marrow is dependent on balanced signaling through this pathway. Moreover, considering the distinct role assigned to BMPRIA and BMPRIB, the temporal gain or loss of a subtype of BMP receptors by MSCs could be critical for commitment and subsequent differentiation (Gimble et al., 1995144).

Wnt signaling in MSCs is also decisive for the reciprocal relationship among the osteo/adipogenic pathways. Activation of the Wnt/p-catenin pathway directs MSCs differentiation towards osteoblasts instead of adipocytes (Bennett et al., 2005; Ross et al., 2000; Moldes et al., 2003). Animal studies have shown that activation of the Wnt signaling pathway increases bone mass, preventing both hormone-dependent and age-induced bone loss (Bennett et al., 2005). Furthermore, Wnt activation may control cell commitment towards osteoblasts by blocking adipogenesis through the inhibition of the expression of both C/EBP and PPARy adipogenic transcription factors, as demonstrated in vivo in humans (Qiu et al., 2007), in transgenic mice expressing Wnt 10b (Bennett et al., 2005) and in vitro (Rawadi et al., 2003). MSCs' self-renewing and maintenance of the undifferentiated state appear to be dependent on appropriate canonical Wnt signaling, promoting increased proliferation and decreased apoptosis (Boland et al., 2004; Cho et al., 2006). The overexpression of LRP5, an essential co-receptor specifically involved in canonical Wnt signaling, has been reported to increase proliferation of MSCs (Krishnan et al., 2006). In addition, disruption in vivo or in vitro of -catenin signaling promoted spontaneous conversion of various cell types into adipocytes (Bennett et al., 2002). Moreover, the importance of this pathway for bone mineral density has been highlighted by the observation that genetic variations at either the LRP5 or Wnt10b gene locus are associated with osteoporosis (Brixen et al., 2007; Usui et al., 2007).

Also, insulin-like growth factor-I (IGF-I) signalling is clearly an important factor in skeletal development. The IGF regulatory system consists of IGFs (IGF-I and IGF-II), Type I and Type II IGF receptors, and regulatory proteins including IGF-binding proteins (IGFBP-1-6) and the acid-labile subunit (ALS) (Rosen et al., 1994). The ligands in this system (i.e. IGFs) are potent mitogens, and in some circumstances differentiation factors, that are bound in the circulation and interstitial fluid as binary (to IGFBPs) or ternary complexes (IGF-ALS-IGFBP-3 or -5) with little free IGF-I or -II. IGF bio-availability is regulated by the interaction of these molecules at the receptor level; hence changes in any component of the system will have profound effects on the biologic activity of the ligand. The IGFBPs have a particularly important role in regulating IGF-I access to its receptor, since their binding affinity exceeds that of the IGF receptors. The IGF system is unique because the IGFBPs are regulated in a cell-specific manner at the pericellular microenvironment, such that small changes in their concentrations could strongly influence the mitogenic activity of IGF-I (Jones and Clemmons, 1995; Hwa and Rosenfeld, 1999; Firth and Baxter, 2002). IGFs are expressed virtually by all tissues, and circulate in high concentrations. Although nearly 80% of the circulating IGF-I comes from hepatic sources, both bone and fat synthesize IGF-I and these tissues contribute to the total circulating pool. Locally produced IGF-I predominates over circulating IGF-I in maintaining skeletal integrity (Rosen et al., 1994; Kawai and Rosen, 2010), and both ALS and IGFBP-3 participate in regulating bone function. However, the possible autocrine/paracrine roles of IGF-I and IGFBPs in marrow (Liu et al., 1993; Peng et al., 2003) or in osteoblast (Zhao et al., 2000; Zhang et al., 2002; Wang et al., 2007) are practically unknown.

RELATIONSHIP BETWEEN THE OSTEO- / ADIPOGENESIS PROCESSES - THE FAT THEORY FOR OSTEOPOROSIS

Since in the bone marrow MSCs are the common precursor cells for osteoblast and adipocytes, adequate osteoblast formation requires diminished adipogenesis. As pointed out above, MSCs commitment and differentiation into a specific phenotype depends on hormonal and local factors (paracrine/autocrine) regulating the expression and/or activity of master differentiation genes (Nuttall and Gimble, 2004; Muruganadan et al., 2009) (Figure 1). A reciprocal relationship has been postulated to exist between the two differentiation pathways whose alteration would facilitate adipose accretion in the bone marrow, at the expense of osteoblast formation, thus decreasing bone mass (Reviewed in Rosen et, al 2009; Rodrguez et al.. 2008; Rosen and Bouxtein, 2006). Such unbalanced conditions prevail in the bone marrow of osteoporosis patients, upsetting MSC activity and the microenvironment (Nuttall and Gimble, 2004; Moerman et al., 2004; Rosen and Bouxtein, 2006). This proposition is known as the fat theory for osteoporosis. Moreover, this alteration of osteo-/adipogenic processes is also observed in other conditions characterized by bone loss, such as aging, immobilization, microgravity, ovariectomy, diabetes, and glucocorticoid or tiazolidindione treatments, highlighting the harmful consequence of marrow adipogenesis in osteogenic disorders (Wronski et al., 1986; Moerman et al., 2004; Zayzafon et al., 2004; Forsen et al., 1999).

Cell studies comparing the differentiation potential of MSCs derived from osteoporotic patients (o-MSCs) with that of control MSCs (c-MSCs) have shown unbalanced osteogenic/adipogenic processes, including increased adipose cell formation, counterbalanced by reduced production of osteogenic cells (Nuttall and Gimble, 2004; Rodrguez et al., 2008; Rosen and Bouxtein, 2006). Further research on MSC differentiation has shown that activation of PPARy2, a master transcription factor of adipogenic differentiation, positively regulates adipocyte differentiation while acting as a dominant negative regulator of osteogenic differentiation (Lecka-Czernik et al., 1999; Jeon et al., 2003; Khan and Abu-Amer, 2003). In contrast, an increase in bone mass density was observed in a PPARy deficient mice model; even the heterozygous deficient animals showed high bone mass and increased osteoblastogenesis (Cock et al., 2004). On the other hand, Runx2 expression by MSCs inhibits their differentiation into adipocytes, as may be concluded from experiments in Runx2-/- calvarial cells, which spontaneously differentiate into adipocytes (Kobayashi et al., 2000).

In vivo observations further support the fat theory. Early studies observed that osteoporosis was strongly associated with bone marrow adipogenesis. Iliac crest biopsies showed that bone marrow from osteoporotic patients had a considerable accumulation of adipocytes in relation to that of healthy elderly women (Moerman et al., 2004; Meunier et al., 1971). More recently, increased bone marrow adiposity measured by in vivo proton magnetic resonance (1H-MRS) has been associated with decreased bone mineral density in patients with low bone density (Griffith et al., 2005; Yeung et al., 2005; Blake et al., 2008).

In newborn mammals there is no marrow fat; however the number of adipocytes increases with age such that in humans over 30 years of age, most of the femoral cavity is occupied by adipose tissue (Moore and Dawson, 1990). The function of marrow fat is largely unknown; in humans it was first considered to be 'filler' for the void left by trabecular bone during aging or after radiation. Later, these cells have been proposed to have a role as an energy source, or as modulators of adjacent tissue by the production of paracrine, and autocrine factors (reviewed in Rosen et al., 2009). In fact, adipokines, steroids, and cytokines (Lee et al., 2002; Pino et al., 2010; Rosen et al., 2009;) can exert profound effects on neighboring marrow cells, sustaining or suppressing hematopoietic and osteogenic processes (Omatsu et al., 2010; Krings et al., 2012; Rosen et al., 2009; Rodrguez et al., 2008).

Thus, the function of bone marrow adipose tissue may be similar to that of extra medullary fat. As such, it has been well established that unbalanced production of signaling products from subcutaneous or visceral fat modulates several human conditions including obesity, lipodystrophy, atherogenesis, diabetes and inflammation. Recent studies in mice, suggest a complex fat phenotype in the bone marrow, presenting mixed brown and white adipose properties (Lecka-Czernik, 2012). Further work is needed to find out whether differences in the quality or quantity of marrow fat, take part in deregulated bone remodelling in some bone diseases.

STUDIES ON THE ACTIVITY OF OSTEOPOROTIC MSCs

Because of their ability to self-renew, human MSCs can be expanded and differentiated in vitro, offering many perspectives for tissue engineering and regenerative medicine approaches. However, there is scarce information on whether specific diseases affect the properties of MSCs, because of the difficult accessibility to human bone marrow in health and disease (Cipriani et al., 2011; Corey et al., 2007).

Our research has focused on the properties of MSCs isolated from bone marrow of control and osteoporotic post-menopausal women. We grouped our observations on functional characteristics of o-MSCs and c- MSCs in three categories, which are summarized in Table I, as follows:

General activities: h-MSCs isolated from osteoporotic and control donors have similar CFU-F, but different proliferation rates. O-MSCs showed significantly diminished proliferation rate and decreased mitogenic response to IGF-I. The pERK/ERK ratio is increased in o-MSCs, compared with control c-MSCs. In other cell types, activation of the MEK/ERK signalling pathway enhances the activity of adipogenic transcription factors (Prusty et al., 2002). We also observed decreased TGF- production by o-MSCs, as well as decreased capacity to generate and maintain a type I collagen-rich extracellular matrix, both conditions supporting cell differentiation into the adipocyte phenotype. Then, considering that the lineage fate of MSCs is dependent on early activation by specific BMPs, PPARy and Wnt signaling (Ross et al., 2000; Rawadi et al., 2003; Westendorf et al., 2004; Baron and Rawadi, 2007), we compared the expression level of some genes related to these pathways in c- and o- MSCs. Results obtained by RT-PCR showed that in c- and o-MSCs the expression level of mRNA for -catenin, Dkk-1, and BMPRIB was similar; while the level of mRNA for Wnt 3a was undetectable in both types of samples. The expression level of mRNA for GSK-3p, LRP6 and Osx was lower in o-MSCs than in c-MSCs, while the mRNA level for Ror2, Wnt 5a, BMPRIA showed doubtful. To further quantify the expression level of GSK-3P, LRP6, Osx, Ror2, Wnt 5a, BMPRIA real time RT-PCR was performed. As shown in Table I, statistically significant decreased mRNA levels for GSK-3p, LRP6 and Osx (0.64, 0.26 and 0.18 fold, respectively) were observed in o-MSCs, as compared to c-MSCs. In addition, mRNA levels for Ror2, Wnt 5a, and BMPRIA were similar in both types of cell samples.

These data suggest impaired regulation by the BMPs and Wnt pathways in o-MSCs, representing some intrinsic deviation from control cells that might underlie the impaired self-renewal, and adipogenic/osteogenic differentiation potential observed in o-MSCs. mRNA levels for Ror2, Wnt 5a, and BMPRIA were similar in both types of cell samples.

STUDIES ON THE ACTIVITY OF BONE MARROW FLUID OF POST-MENOPAUSAL WOMEN

Distinctive environmental bone marrow conditions appear to support the development and maintenance of the balance between bone resorption and bone formation. Knowledge is scarce about the intramedullar concentration of compounds with recognized regulatory effects on bone formation or resorption and is limited to some pathologic conditions or estimated from measurements in plasma (Wiig et al., 2004; Iversen and Wiig, 2005; Lee et al., 2002; Khosla et al., 1994).

Measurement of soluble molecules found in human bone marrow has been particularly difficult, not only because of tissue seclusion, but also because of the complicated anatomy and blood perfusion of bone. Since it may be expected that concentrations measured in the bone marrow fluid (BMF) more reliably reflect the physiologically relevant levels in the interstitial compartment surrounding the bone cells than values found in blood, we isolated the extracellular bone marrow fluid by directly spinning bone marrow samples for 20 min at 900xg. Considering the complex organization in such a regulatory milieu, we opted for evaluating some molecules recognized as markers of adipocyte, proinflammatory or osteoclastic/osteoblastic activity (Pino et al., 2010).

The concentrations of cytokines or receptors measured in the bone marrow extracellular fluid from control and osteoporotic human donors are indicated in Table II. In addition, the concentrations of IGF-I and its IGFBPs were analyzed, as well as the C-terminal telopeptide cross-links of type I collagen (CTX). Results summarized in Table II indicate significantly different concentrations of regulatory molecules in the extracellular fluid of control versus osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic samples showed decreased leptin bioavailability, suggesting that insufficient leptin action may characterize the osteoporotic bone marrow (Pino et al., 2010). In addition, bioavailability of IGF-I appears diminished in o-BMF, as shown by the increased IGFBP3/IGF-I ratio.

TABLE II

Regulatory activity in bone marrow fluid of post-menopausal women

Taken together our results and those of other researchers identify significant differences between functional properties of control and osteoporotic MSCs, displayed in vitro, in cells under basal or differentiating conditions. Moreover, it can be concluded that such divergence prevails also in vivo, because the bone marrow fluid of osteoporotic patients characterizes by unfavourable content of several regulatory molecules. Therefore, the properties of both MSCs and bone marrow microenvironment are significantly impaired in osteoporotic patients, negatively affecting bone formation.

CONCLUSIONS

In the pathogenesis of osteoporosis, impairment of both MSCs functionality and microenvironment add to the known detrimental effect of increased osteoclast activity, resulting in decreased bone formation.

O-MSCs are characterized by intrinsic functional alteration leading to poor osteogenic capability and increased adipogenesis. Osteoporotic bone marrow microenvironment differs from the control microenvironment by increased concentration of pro-adipogenic and pro-inflammatory regulatory factors.

The content and/or quality of adipocytes in the bone marrow appear critical to delineate impairing of MSCs; in this sense osteoporosis could be homologated to other age-related diseases such as obesity, atherogenesis and diabetes, which are characterized by extramedullar unbalanced adipocyte formation and signaling.

Currently it is not known how damaged o-MSCs emerge, further work is needed to ascertain the role of the microenvironment, and genetic and epigenetic factors, as proposed for other stem cells-related pathologies.

The conclusion that intrinsic properties of MSCs are altered in osteoporosis should be relevant for the therapeutic use of MSCs, which represent an interesting promise for regenerative medicine for several severe human diseases.

The possibility of reversing o-MSCs impairment opens new perspectives for osteoporosis therapy.

ACKNOWLEDGEMENTS

We thank Dr. Mariana Cifuentes for her critical review of the manuscript and valuable comments. This work was supported by a grant from the Fondo Nacional de Ciencia y Tecnologa (FONDECYT # 1090093)

REFERENCES

ASTUDILLO P, ROS S, PASTENES L, PINO AM, RODRGUEZ JP (2008) Increased adipogenesis of osteoporotic human-msenchymal stem cells (MSCs) characterizes by impaired leptin action. J Cell Biochem 103: 1054-1065[Links]

BAKSH D, SONG L, TUAN RS (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8: 301-316. [Links]

BARON R, RAWADI G (2007) Minireview: Targeting the Wnt/-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635-2643. [Links]

BENNETT CN, LONGO KA, WRIGHT WS, SUVA L J, LANE TF, HANKENSON KD, MACDOUGALD OA (2005). Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102: 3324-3329. [Links]

BENNET CN, ROSS SE, LONGO KA, BAJNOK L, HEMATI N, JOHNSON KW, HARRISON SD, MACDOUGALD OA (2002) Regulation of Wnt signaling during adipogenesis. J Biol Chem 277:30998-31004. [Links]

BIANCO P, ROBEY PG (1999) Diseases of bone and stromal cell lineage. J Bone Miner Res 14: 336-41. [Links]

BLAKE GM, GRIFFITH JF, YEUNG DK, LEUNG PC, FOGELMAN I (2008) Effect of increasing vertebral marrow fat content on BMD measurement, T-Score status and fracture risk prediction by DXA. Bone 44: 495-501[Links]

BOLAND GM, PERKINS G, HALL DJ, TUAN RS (2004) Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 93:1210-1230. [Links]

BRIXEN K, BECKERS S, PEETERS A, PITERS E, BALEMANS W, NIELSEN TL, WRAAE K, BATHUM L, BRASEN C, HAGEN C, ANDERSEN M, VAN HUL W, ABRAHAMSEN B (2007) Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) genes are associated with peak bone mass in non-sedentary Men: results from the Odense Androgen Study. Calcif Tissue Int 81:421-429. [Links]

CHO HH, KIM YJ, KIM SJ, KIM JH, BAE YC, BA B, JUNG JS (2006) Endogenous Wnt signaling promotes proliferation and suppresses osteogenic differentiation in human adipose derived stromal cells. Tissue Eng 12:111-121. [Links]

CIPRIANI P, MARRELLI A, LIAKOULI V, DI BENEDETTO P, GIACOMELLI R (2011) Cellular players in angiogenesis during the course of systemic sclerosis. Autoimmunity Rev 10:641-646. [Links]

COCK TA, BACK J, ELEFTERIOU F, KARSENTY G, KASTNER P, CHAN S, AUWERX J (2004) Enhanced bone formation in lipodystrophic PPARhyp/hyp mice relocates haematopoiesis to the spleen. EMBO reports 5: 1007-1012. [Links]

COREY SJ, MINDEN MD, BARBER DL, KANTARJIAN H, WANG JCY, SCHIMMER AD (2007) Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer 7: 118-129. [Links]

FIRTH SM, BAXTER RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824-854. [Links]

FORSEN L, MEYER HE, MIDTHJELL K, EDNA TH (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia 42: 920-925. [Links]

FRIEDENSTEIN AJ, CHAILAKHJAN RK, LALYKINA KS (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393-403[Links]

GIMBLE JM, MORGAN C, KELLY K, WU X, DANDAPANI V, WANG CS, ROSEN V (1995) Bone morphogenetic proteins inhibit adipocyte differentiation by bone marrow stromal cells. J Cell Biochem 58: 393-402. [Links]

GORI F, THOMAS T, HICOK KC, SPELSBERG TC, RIGGS BL (1999) Differentiation of human marrow stromal precursor cells: bone morphogenetic protein-2 increases Osf2/Cbfa1, enhances osteoblast commitment, and inhibits late adipocyte maturation. J Bone Miner Res 14: 1522-1535. [Links]

GRIFFITH JF, YEUNG DK, ANTONIO GE, LEE FK, HONG AW, WONG SY, LAU EM, LEUNG PC (2005) Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy. Radiology 236: 945-951. [Links]

HAIYAN H, TAN-JING S, LI X, HU L, HE Q, LIU M, LANE MD, TANG QQ (2009) BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 106:12670-12675. [Links]

HESS R, PINO AM, ROS S, FERNNDEZ M, RODRGUEZ JP (2005) High affinity leptin receptors are present in human mesenchymal stem cells (MSCs) derived from control and osteoporotic donors. J Cell Biochem 94:50-57. [Links]

HOFER EL, LABOVSKY V, LA RUSSA V, VALLONE VF, HONEGGER AE, BELLOC CG, WEN HC, BORDENAVE RH, BULLORSKY EO, FELDMAN L, CHASSEING NA (2010) Mesenchymal stromal cells, colony-forming unit fibroblasts, from bone marrow of untreated advanced breast and lung cancer patients suppress fibroblast colony formation from healthy marrow. Stem Cells Dev 19: 359-370. [Links]

HWA V, OH Y, ROSENFELD RG (1999) The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 20:761-787[Links]

IVERSEN PO, WIIG H (2005) tumor necrosis factor a and adiponectin in bone marrow interstitial fluid from patients with acute myeloid leukemia inhibit normal hematopoiesis. Clin Cancer Res 11:6793-6799. [Links]

JEON MJ, KIM JA, KWON SH, KIM SW, PARK KS, PARK SW, KIM SY, SHIN CS (2003) Activation of peroxisome proliferator-activated receptor-y inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. J Biol Chem 278: 23270-23277. [Links]

JONES JI, CLEMMONS DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3-34. [Links]

KAWAI M, ROSEN CJ (2010) The IGF-I regulatory system and its impact on skeletal and energy homeostasis. J Cell Biochem 111:14-19. [Links]

KHAN E, ABU-AMER Y (2003) Activation of peroxisome proliferator-activated receptor-y inhibits differentiation of preosteoblasts. J Lab Clin Med 142: 29-34. [Links]

KHOSLA S, PETERSON JM, EGAN K, JONES JD, RIGGS BL (1994) Circulating cytokine levels in osteoporotic and normal women. J Clin Endocrinol Metab 79:707-611. [Links]

KOBAYASHI H, GAO Y, UETA C, YAMAGUCHI A, KOMORI T (2000) Multiline-age differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 273: 630-636. [Links]

KOLF CM, CHO E, TUAN RS (2007) Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation Arthritis Research & Therapy 9:204 -213. [Links]

KRINGS A, RAHMAN S, HUANG S, LU Y, CZERNIK PJ, LECKA-CZERNIK B (2012) Bone marrow fat has browne adipose tissue characteristics, which are attenuated with aging and diabetes. Bone 50: 546-552. [Links]

KRISHNAN V, BRYANT HU, MACDOUGALD OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116: 1202-1209. [Links]

KUHN NZ, TUAN RS (2010) Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis. J Cell Physiol 222: 268-277. [Links]

KULTERE B, FRIEDL G, JANDROSITZ A, SNCHEZ-CABO F, PROKESCH A, PAAR C, SCHEIDELER M, WINDHAGER R, PREISEGGER KH, TRAJANOSKI Z (2007) Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics 8: 70-84. [Links]

LECKA-CZERNK B (2012) Marrow fat metabolism is linked to the systemic energy metabolism. Bone 50: 534-539. [Links]

LECKA-CZERNIK B, GRINNELL SJ, MOERMAN EJ, CAO X, MANOLAGAS SC, OBRIEN CA (1999) Identification of a Smad binding element in the PPARy2 promoter: A potential site of cross-talk between osteoblastogenesis and adipogenesis signaling pathways. J Bone Miner Res 14: Suppl1, S1056. [Links]

LECKA-CZERNIK B, GUBRIJ I, MOERMAN EA, KAJKENOVA O, LIPSCHITZ DA, MANOLAGAS SC, JILKA RL (1999) Inhibition of Osf2/Cbaf1 expression and terminal osteoblast differentiation by PPAR-gamma2. J Cell Biochem 74: 357-371. [Links]

LEE WY, KANG MI, OH ES, HAN JH, CHA BY, LEE KW, SON HY, KANG SK, KIM CC. (2002) The role of cytokines in the changes in bone turnover following bone marrow transplantation. Osteoporos Int 13:62-68. [Links]

LI J, TSUJI K, KOMORI T, MIYAZONO K, WRANA JL, ITO Y, NIFUJI A, NODA M (1998) Smad2 overexpression enhances smad4 gene expression and suppresses Cbfa1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells. J Biol Chem 273: 31009-31015. [Links]

LI X, SHET K, RODRIGUEZ JP, PINO AM, KURHANEWICZ J, SCHWARTZ A, ROSEN CJ (2012) Unsaturation Level Decreased in Bone Marrow Lipids of Postmenopausal Women with Low Bone Density Using High Resolution HRMAS NMR. ASBMR 2012 Annual Meeting American Society of Bone and Mineral Research. October 12-15, 2012, Minneapolis, Minnesota, USA. [Links]

LIN NH, MENICANIN D, MROZIK K, GRONTHOS S, BARTOLD PM (2008) Putative stem cells in regenerating human periodontium. J Periodont Res 43: 514-523. [Links]

LINDNERA U, KRAMERA J, ROHWEDEL J, SCHLENKE P (2010) Mesenchymal stem or stromal cells: toward a better understanding of their biology? Transfus Med Hemother 37:75-83[Links]

LIU JP, BAKER J, PERKINS AS, ROBERTSON EJ, EFSTRATIADIS A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59-72. [Links]

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Resident Asma Mursleen, MD (center) with Roseanne C. Berger, MD (left), and Michael E. Cain, MD was honored for her research at the 20th annual Scholarly Exchange Day.

Published August 30, 2017

Trainees and a student in the departments of Medicine, BiomedicalEngineering and Pediatrics havereceived awards for their research.

Hem-Onc, Medicine Trainees Receive Frawley

The two trainees to receive support from theThomasF. Frawley, MD, Residency Research FellowshipFundare:

Asma Mursleen, MDResident in theDepartment ofMedicineProject Title: Defining the Role of CDC-derived Exosomes onMacrophage Polarization and Modulation of CardioprotectionFollowing Myocardial Infarction

Amanda Przespolewski, DOA 2017 alumna of the hematology/oncologyfellowshipProject title: Dual Enhancement of Immune Responses andInhibition of Marrow Vasculature in Acute MyeloidLeukemia

The awardsupports medical or surgical residents, fellowsand new graduates for whom research represents a primary interestand passion.

Frawley, a 1944 graduate of the medical school, was a nationallyrecognized endocrinology researcher, president of the AmericanCollege of Physicians and chair of medicine at Saint LouisUniversity School of Medicine.

Student and Faculty Member Win Mindell/Brody

The 2017 recipients of the EugeneR. Mindell, MD, and Harold Brody, MD 61, PhD, ClinicalTranslational Research Awardare:

YonghoBae, PhD Assistant professor in theDepartment ofPathology and Anatomical Sciences Project Title: Effect of Arterial Stiffening onVascular Smooth Muscle Cell Mechanotransduction

Kyle Indiana MentkowskiMasters candidate in the Departmentof Biomedical EngineeringProject Title: Development of a Targeted CardiomyocyteDelivery System Utilizing Cardiosphere-Derived CellExosomes

The award recognizes junior research scientists for the bestbasic science research that seeks to solve a clinical problem.

Mindell chairedUBs Department ofOrthopaedics from 1964 to 1988. A past president of theAmerican Board of Orthopaedic Surgery, he is creditedwithinitiating the boards certifying process fororthopaedic surgeons.

Brody was the chair of anatomy and cell biology from 1971 to1992. He founded UBs BrainMuseum, a world-class collection of brain specimens andslides.

Pediatrics, Medicine Residents Receive Calkins

The 2017 honorees for the EvanCalkins, MD, Fellowship for Community-BasedResearchare:

Raed Al Yacoub, MD Resident in the Department ofMedicineProject Title: Enhancing the Prevention of MicrovascularComplications of Diabetes Type 2: A Resident-Led QIProject

Prerana Baranwal, MDResident in the Department ofPediatricsProject Title: Addressing Childhood Obesity ThroughDyslipidemia Screening: Measuring Frequency of DyslipidemiaScreening with Substitution of Random Lipid Panel for Fasting LipidPanel

The award supports residents, fellows and junior faculty whoconduct community-based research or quality improvementprojects.

Calkins was chair of the UB Department of Internal Medicine,division chief of geriatrics and founder of the geriatricsfellowship. He served as director of medicine at Meyer MemorialHospital (now Erie County Medical Center) for 12 years.

The award is a product of his conviction that medicalinstitutions have an obligation to improve the quality of, andaccess to, health care throughout the community.

Fellow Receives Honorable Mention

Amro Elshoury, MBBCh, a trainee in the hematology/oncologyfellowship, received an honorable mention for the Frawleyaward. Elshourys project was: The Effect ofExtra-Physiologic Oxygen Shock / Stress (EPHOSS) On Human BoneMarrow Stem Cell Viability And Multi-Potency.

Awards Presented at Scholarly Exchange Day

RoseanneC. Berger, MD, senior associate dean for graduate medicaleducation, presented the awards at this years ScholarlyExchange Day.

The keynote speaker,StevenD. Schwaitzberg, MD, professor and chair of surgery,presented a talk titled Preparing Students and Residents for21st Century Surgery.

MichaelE. Cain, MD, vice president for health sciences and dean, Jacobs School of Medicine andBiomedical Sciences, gave school updates and introductoryremarks at the event.

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Frawley, Mindell/Brody, Calkins Awards Recognize 5 for Excellence - UB School of Medicine and Biomedical Sciences News

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Natural Skin Care Authority MyChelle Launches at Nationwide Department Store - PR Newswire (press release)

Skin Stem Cells Comments Off on Natural Skin Care Authority MyChelle Launches at Nationwide Department Store – PR Newswire (press release) | August 30th, 2017

A human stem cell replicating itself.

Hal X. Nguyen and Aileen J. Anderson

But when it comes to spinal cord injuries, the healing process goes awry.

Immune cells rush in and cause a scar that blocks the ability of neurons to regrow and reconnect. However, recent studies have shown that the immune system can also aid regeneration.

The immune system has both positive and a negative impact what it does is really context specific, says Jan Kaslin, who studies neural regeneration in zebrafish at the Australian Regenerative Institute of Medicine in Melbourne, Australia.

Stem cells provide a great hope for damaged spinal cords and brain injury but it has not been clear on how the immune system may affect the regrowth.

Now a new study has taken a look at how stem cells and the immune system interact in the repair of the spinal cord. Led by Aileen Anderson from the University of California, Riverside and published in the Journal of Neuroscience, the study suggests that whether or not the immune system hinders or helps transplanted stem cells to regrow lost tissue may be influenced by the presence of certain kinds of immune cells.

The study used stem cells derived from human foetal brain tissue and transplanted them into mice with a wound in their spinal cord. They then blocked the invasion of a specific population of immune cells called neutrophils and observed how well the wound was repaired by transplanted the stem cells.

In contrast to earlier research, Andersons team found with that with neutrophils out of the way the wound healed more easily, requiring few stem cells.

This is the first data to show that the immune environment can be altered to allow stem cell populations to perform better in terms of restoring function, according to Anderson.

Can other immune cells be manipulated to increase the effectiveness of stem cell transplantation in spinal cord regeneration?

These findings are an important of piece of the puzzle, says Kaslin, that may significantly improve future stem cell transplantation approaches.

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Immune cells may prevent stem cell growth in spinal cord repair - Cosmos

Spinal Cord Stem Cells Comments Off on Immune cells may prevent stem cell growth in spinal cord repair – Cosmos | August 28th, 2017

By: Barbara McClure, RN, BSHA | A Defined Image, Med SpaPublished: 2017-08-26 23:01Date Modified: 2017-08-26 23:01

A Breakthrough approach to skin rejuvenation ProCell Therapies brings together professional Dermabrasion & Microchanneling technology with Stem Cell science and the Procell device for an exciting new approach to skin rejuvenation.

Clinical studies prove that this breakthrough treatment achieves better results with shorter recovery time than far more invasive & expensive procedures such as fractional lasers and deep chemical peels for fine lines, scars, acne, acne scarring, sun damage & laxity.

ProCell Therapies are the perfect complement to facial fillers, neurotoxin injections, and deeper skin tightening procedures, like fractional CO2 resurfacing and RF microneedling.

How does Procell Work?Dermabrasion & Microchanneling with Procell stimulates the basal layer of the epidermis that produces keratinocytes to increase production of new collagen and elastin through the release of growth factors and cytokines. Unlike more aggressive treatments like fractional lasers and chemical peels that injure the skin to cause a healing response, Procell triggers the gene expression of growth factors, peptides and cytokines with minimal to no damage to the dermis. These sophisticated, organic, autologous electro-chemical compounds increase production of collagen and elastin for firmness, elasticity, and texture & tone. Procell works wonderfully in combination with microdermabrasion. Livra Stem Cytokine serums are applied during and after treatment to penetrate the skin and deliver high concentrations of growth factors that enhance production of healthy new skin.

Unlike growth factor serums made from other sources, Procells Livra serums are derived from mesenchymal stem cells that produce the full array of peptides, growth factors and cytokines specifically for regeneration of healthy, new skin!. For more information and to schedule an appointment, call 770-978-0956

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Introducing ProCell Therapies Dermabrasion, Microchanneling, and Stem Cell Therapy - Gwinnett Citizen

Skin Stem Cells Comments Off on Introducing ProCell Therapies Dermabrasion, Microchanneling, and Stem Cell Therapy – Gwinnett Citizen | August 27th, 2017

Jack Massey is ready to go back to school.

Only this time, the University of Florida senior will head back to campus with his mom and a new outlook on life.

Massey suffered a spinal cord injury in a pool accident in March and is paralyzed from the chest down. After months of rehab, he's eager to get back into a familiar routine.

"It's definitely boring," the 21-year-old said at his parents' home in Niceville. "There's not a lot to do. I want to go back to school. I still have my brain. I still have everything I need to be successful."

After the accident March 17, Massey was treated at the University of Florida Shands Hospital and then was transferred to Shepherd Center, a spinal cord and brain injury rehab center in Atlanta. At Shepherd Center he met with a peer mentor, counselors and physical therapists to help him find a new normal.

Jack has remained positive throughout the past six months.

"Jack has been a fighter through all of this," said his mother, Julie. "I think he's done well. I only saw him break down once."

Before the accident, Jack was a well-rounded athlete who playing baseball and basketball and ran. He was a star on the track and field team at Niceville High School, with his 4 X 800 relay winning state his senior year.

He says the biggest challenge now is not being able to do the same things he could before.

"I can't get up and go," he said. "It didn't really start to set in until after I got out of rehab."

Jack has had to find enjoyment in other things, like reading or playing with the dogs. His friends have learned to transfer him from his wheelchair to a car so they can take him to the movies or out to eat. When they recently took a trip to the beach, Julie said five of Jack's friends carried him out to the sand a lesson on how hard it is to navigate the world in a wheelchair.

Jack said he believes technology one day will advance enough that he won't be paralyzed forever. He also volunteered to do stem cell surgery to allow doctors to study the effects of stem cells on his spine for the next 15 years. Instead of wallowing in self-pity, he's moving forward. But he'll need help.

"I'm appreciating everything in the now," he said.

Doctors have said Jack has adapted faster than expected, but there are still some everyday essential tasks that are out of his reach. He cannot write or cook. He can shower himself but can't dry himself or transfer himself in and out of his wheelchair. The Massey family hopes to secure a personal care attendant for Jack at school, but until then Julie will be in Gainesville to help him transition. An occupational therapy student from the university will also help Jack on a temporary basis.

Finding proper care for her son has proven to be a learning experience for Julie and her husband, Lance.

"I don't know how people do it," she said. "We have good health care, but then there's hidden costs. There's travel expenses. ... It's kind of humbling. Nobody should have to go to GoFundMe for medical help."

Jack wants to spend his final year as an undergrad as independent as possible. After months of helping him recover, Julie said it will be hard to let her son go. Jack is the oldest of three; his brother Lance is 19 and a student at UF and his sister Alina is 14 and attends Ruckel Middle School.

"It's like letting him go off to kindergarten again," she said.

As for life after college, Jack said he doesn't feel limited in career choices. One of his professors in the geology department encouraged him by saying that there were plenty of opportunities he could pursue in that field. Jack said he may also consider law school. One thing he's learned through this life-altering experience is that there are no limits to what he can achieve.

"I haven't done that much deep thinking. I just go with the flow," he said. "But I learned I have more perseverance. I'm more mentally tough than I thought I was. I'm appreciative for life in general. That's one of the big things."

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Paralyzed after pool accident, student heads back to college | News ... - News & Observer

Spinal Cord Stem Cells Comments Off on Paralyzed after pool accident, student heads back to college | News … – News & Observer | August 27th, 2017

The idea of bringing people back from the dead could one day be more than just science fiction it could be a reality. Over the past few decades, there has been progress in keeping people alive via advanced surgical techniques, organ transplants, mechanical ventilators and even saving a beating heart that has once stopped. However, when it comes to the injured brain, stem cell therapy may show promise in bringing the brain dead back to life.

In BrainCraft's video, "Ways to Bring the Brain Dead Back to Life" host Vanessa Hill explains the brain is made up of trillions of connections; our life depends on these connections. If the heart stops pumping blood for a few minutes, the brain will fall into a state of frenzy where some neurons starve to death during the blackout and others fight for life. Neurotransmitters spill out neurons in high concentrations, which leads to uncontrollable electrical changes sweeping across the brain, causing toxic chemicals to pile up and burn holes in the membranes of neurons.

All of these events lead to programmed cell death. Neurons start to die one by one, until the brain stops functioning altogether.However, scientists have started to discover the brain does have a small reservoir of stem cells that can generate new neurons.

Researchers have hypothesized whether these cells could be coaxed to turn into new neurons that self-repair the brain's injured tissue. They have also theorized the possibility of injecting neural stem cells into the brain of a patient. So, if it becomes possible to replace dead neurons, it should be possible to resurrect a person via stem cell therapy who just died.

Previous research has shown it's possible to plant stem cells in the brains of mice and help them grow into fully functioning neurons that make connections with their neighbors. In the future, these methods could be used to repair the damage done to the brain by a stroke. Currently, several trials are underway to transplant new neurons into the brains of people with Parkinson's disease.

A Philadelphia-based company, Bioquark, hopes to use stem cells to reverse death by injecting them into the spinal cords of people who have been declared clinically brain dead. The subjects will also receive an injected protein blend, electrical nerve stimulation, and laser therapy directed at the brain. The ultimate goal is to grow new neurons and spur them to connect to each other, which can potentially bring the brain back to life.

Theres the potential thata cocktail of moleculesto spurr neuronal growth could come in pill form.

This concept does raise a lot of questions, like Will we be a different person if brand new neurons connect differently? Or ,How many cells can be replaced without fully becoming a whole different person?

Stem cells are currently used for a variety of conditions, from stroke to paralysis.

But, there's currently no FDA-approved stem therapy for brain conditions. Scientists are hopeful if this approach worked on mice, it could one day work on humans too.

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The Possible Ways To Bring Brain-Dead Patients Back To Life - Medical Daily

Spinal Cord Stem Cells Comments Off on The Possible Ways To Bring Brain-Dead Patients Back To Life – Medical Daily | August 25th, 2017

Erica Honoway is scheduled to speak at the annual "Run for Mandi" charity event in Saskatoon, after her son Lincoln was saved by a bone marrow transplant.Michael Bell / Regina Leader-Post

An annual run honouring a late Canadian hockey player is working with a bone marrow and stem cell registry group in hopes of helping more people in her name.

The Run for Mandi is named for Saskatchewan hockey player Mandi Schwartz, who was diagnosed with acute myeloid leukemia in 2008 while she was part of the Yale Bulldogs hockey team. She died in 2011.

The event kicks off Sunday afternoon at River Landing. The five-kilometre run and the one-kilometre family walk will start at two, and for the first time a bone marrow and stem cell registry group will be set up at the run.

Mandis mother, Carol Schwartz, said shes proud of the work being done by the Mandi Schwartz Foundation in her daughters name.

It just makes these events more meaningful lives are being saved, Schwartz said. Theres probably no greater gift than meeting someone who got a successful match.

The OneMatch Stem Cell and Marrow Network, a part of Canadian Blood Services, will accept registrations at Sundays event. Schwartz said theyve handed out information before, but this is the first time OneMatch will swab volunteers at the event to register them in the network.

Bobbylynn Stewart with Breck Construction, the title sponsor for the event, said she has a personal stake in helping organize the run because her mother also died of acute myeloid leukemia. Its a chance for the company and the community to help other families with similar struggles, she said.

When you have a blood cancer or disorder, often times you are relying on a stem cell match through the network, Stewart said. So growing that network is vital.

Alongside the run will be a charity silent auction and a barbecue. Mandis brothers, professional hockey players Jayden and Rylan Schwartz, are also expected to attend, along with NHL players Ryan Murray and JC Lipton, and AHL player Brandon Gormley.

Erica Honoway, scheduled to speak before the run, said she is haunted by how close her family came to sharing in the Schwartzs tragedy.

Her son Lincoln was diagnosed with aplastic anemia last year, but a bone marrow transplant helped save his life.

In all the registries in the world, they found two matches for Lincoln, Honoway said. Every single person who gets on is another chance for someone to have their life saved.

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Annual 'Run for Mandi' hosting bone marrow registry to combat cancer - Saskatoon StarPhoenix

Bone Marrow Stem Cells Comments Off on Annual ‘Run for Mandi’ hosting bone marrow registry to combat cancer – Saskatoon StarPhoenix | August 25th, 2017

Madalayna and Tamara Ducharme, 33 days after Madalayna received her bone marrow transplant. Photo provided by Tamara Ducharme) By Adelle LoiselleAugust 25, 2017 5:10am

Six months ago, Windsor residents came out in droves to help baby Madalayna Ducharme find a bone marrow match.

Saturday, they can help again by taking part in a bowl-a-thon dedicated to supporting the families of those who still need a transplant.

The 12th annual Bowling for Bone Marrow Bowl-a-Thon takes place Saturday at Rose Bowl Lanes on Dougall Ave. in Windsor. Check-in is at noon, and the fundraiser gets underway at 1pm.

It is the Katelyn Bedard Bone Marrow Associations biggest fundraiser of the year, and this year it can count Madalayna among its success stories.

The baby girl, who celebrated her first birthday this week, likes to dance and can stand while holding her parents fingers. Her mother, Tamara Ducharme is grateful for every day.

We were unsure if we were going to make it there, to the first birthday, she says. Were hoping that shell be a healthy little girl.

However, the struggle is not over. Friday, the family is driving up Hwy. 401 for Madalaynas six-month post-transplant appointment at Sick Kids Hospital in Toronto.

Ducharme says her daughter has bi-weekly hospital visits to ensure her medication is up to date. Madalayna still uses a feeding tube, and even months later, there is still the question whether the bone marrow transplant from her brother is working.

Theyll probably do an x-ray, says Ducharme about the upcoming appointment. Shes had a little growth. If her bones show changes that means shes on the track of getting better. Now, if there is no change, I dont know what were going to do.

Life with a young child who has received a transplant can also be very isolating, and Ducharme admits it has not been easy.

Were bubbled. We really go anywhere. We dont really play with other kids, she says. Youve gotta take the proper steps to take care of your child. If she could catch anything and it could be really detrimental.

She says the association has been very good to her family and they are grateful for their, and the communitys support over a challenging chapter in their lives.

Bryan and Joanne Bedard understand the difficulties faced by families of children waiting for a donor. They lost their three-year-old daughter, Katelyn in 2005 at the age of 3 when they were unable to find one.

Since then, they have raised money for donor clinics and awareness of the OneMatch Stem Cell and Marrow Network which now has 6,500 registered donors. The Katelyn Bedard Bone Marrow Association has also donated $115,000 to stem cell and bone marrow transplant research at both the University of Windsor and the Universite de Montreal.

With files from Maureen Revait

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Bowl-A-Thon For Stem Cell Bone Marrow Transplant Recipients - BlackburnNews.com

Bone Marrow Stem Cells Comments Off on Bowl-A-Thon For Stem Cell Bone Marrow Transplant Recipients – BlackburnNews.com | August 25th, 2017

Vitamin C may prompt faulty stem cells in bone marrow to die off, rather than multiplying to spur blood cancers.

A new study has found that vitamin C may communicate to faulty stem cells within bone marrow that they should mature and perish in a normal manner rather than multiplying to spur blood cancers. This is the insight gleaned from a study spearheaded by NYU Langone Health Perlmutter Cancer Center researchers. Study details were recently published in Cell.

About the Findings

The authors of the study state specific genetic alterations are known to decrease the ability of an enzyme referred to as tet methylcytosine dioxygenase 2 (TET2) to promote stem cell maturation and death in patients who have specific types of leukemia. They determined vitamin C activates TET2 functionality in mice designed to lack the enzyme. It is possible that vitamin C will prove to be a safe and effective treatment for diseases spurred by leukemia stem cells deficient in TET2. It is likely that vitamin C will be used in combination with other targeted therapies.

Study Details

The researchers used genetically altered mice in which TET2 was turned off. These mice endured abnormal stem cell activity. Such changes were reversed when a genetic trick restored TET2 expression. Providing high doses of vitamin C functioned similarly to restoring TET2 functionality on a genetic level. Vitamin C's promotion of DNA demethylation caused stem cells to mature and limited the advancement of leukemia cancer stem cells from humans that were implanted in mice. Vitamin C treatment affected leukemic stem cells similar to damaged DNA. Vitamin C was used in combination with a PARP inhibitor to produce an enhanced effect on such stem cells, sending them from self-renewal to maturity and subsequent death.

TET2 and Cancer

Alterations in the genetic code that decrease TET2 functionality are found in 10% of those who have acute myeloid leukemia (AML). About one-third of patients with a form of preleukemia known as myelodysplastic syndrome and upwards of half of those with chronic myelomonocytic leukemia have such genetic code mutations. These cancers spur anemia, bleeding and infection risk as abnormal stem cells multiply within bone marrow until they block the production of blood cells. Recent tests show about 2.5% of cancer patients living in the United States might develop TET2 alterations. This includes some patients with solid tumors and lymphomas.

About Cell Death Switch

The results of the study center on the relationship between cytosine and TET2. Cytosine is one of the several letters of nucleic acidthat make up genes' DNA code. Each cell type has thesame genes yet each receives unique instructions to turn on only those required in a specific cellular context. Examples of such epigenetic mechanisms include DNA methylation. This is an attachment of a diminutive molecule to cytosine bases to put a halt to the action of a gene containing them. Gene expression within stem cells is fine-tuned when methyl groups are attached and removed. Stem cellexpressions can then mature and multiplyto form muscle, nerve, bone and other types of cells. The bone marrow holds stem cell pools as adulthood is reached until they can become replacement cells. Inpatients with leukemia, signals that typically tell blood stem cells to mature end up malfunctioning. This allows for endless multiplication and a self-renewing rather than the generation of regular white blood cells required to combat infection.

TET2 empowers an alteration in the molecular structure of methyl groups required for their removal from cytosines. Such demethylation activates genes that direct stem cells to mature and commence a countdown to self-destruction as a component of regular turnover. This functions as a means of combating cancer yet it is disrupted in blood cancer patients who have TET2 mutations.

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Vitamin C May Help Slay Blood Cancer Stem Cells - Anti Aging News

Bone Marrow Stem Cells Comments Off on Vitamin C May Help Slay Blood Cancer Stem Cells – Anti Aging News | August 22nd, 2017

How long do you expect to live?

Thats a question that can make a lot of people feel suddenly lost for an answer.

In fact, its not a question that anybody would like to answer.

However, for scientific, socio-economic, and other legitimate reasons, average life expectancy per region are being documented. According to the World Factbook by the Central Intelligence Agency, the average life expectancy at birth of the following countries as of 2016 are as follows:

The rest of the world has an average life expectancy of 80 years downwards, with Chad ranking the lowest at 50.20 years.

Life is short, too short.

Its the reason why the pursuit of anything and everything under the sun that can stop aging is mankinds obsession.

We want to live longer; if possible, forever.

Forever is definitely too, too far away. But, longer, yes. Its more probable.

Heres the latest news on anti-aging, and this time its about stem cells. Stem cells from a young heart may help in regaining vitality which we lose as we grow old.

Researchers from the Cedars-Sinai Heart Institute have recently discovered that upon application of Cardiosphere-derived cells (CDC), which they took from newborn mice and injected into the hearts of 22-month-old mice, had resulted to better heart functionality, hair regrowth at a faster rate, 20 percent longer exercise endurance, and longer cardiac telomeres.

The findings on the effect of CDC cells on telomeres is very significant since these compound structures located at the tip of chromosomes function as the cells time-keepers. In fact, another study is focusing on methods to lengthen telomeres to fight the effects of progeria and help prolong life.

Our previous lab studies and human clinical trials have shown promise in treating heart failure usingcardiac stem cell infusions, saidCedars-Sinai Heart Institute and lead researcher Eduardo Marbn, MD, PhD, Now we find that these specialized stem cells could turn out to reverse problems associated with aging of the heart.

According to Dr. Marban, the CDC cells work on reversing the aging process by secreting very small vesicles that are full of signaling molecules like proteins and ribonucleic acid (RNA). The vesicles appear to have all the necessary information in producing cardiac and systemic rejuvenation.

In 2009, the LA-based team achieved the worlds first stem cell infusion which they hope to use in treating patients with Duchenne muscular dystrophy and cases of heart failure with preserved ejection fraction. However, this was the first time that they have observed this kind of rejuvenating effects of CDC cells.

Nevertheless, Dr. Marban and his team acknowledge that they still have a lot to do and figure out. They havent determined yet if the CDC cells could lengthen life, or just produce a younger heart in an aged physique. They also have to find out if the cells must come from younger hearts for the stem cell treatment to be effective.They will obviously need more time and tests to find the right answers to these very important questions.

But, if Dr. Marban and his team succeed, CDC cells may be a key to restoring youth and vigor. It will also help globally the large number of people who suffer from cardiovascular diseases-heart disease is the worlds number 1 killer and accounts for 17.3 million deaths per year.

The study was published on theEuropean Heart Journal.

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In World First, Scientists Reverse Aging in Old Hearts by Injecting Younger Cells - Wall Street Pit

Cardiac Stem Cells Comments Off on In World First, Scientists Reverse Aging in Old Hearts by Injecting Younger Cells – Wall Street Pit | August 20th, 2017

Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics

Over the past few years, the regulatory landscape for cell therapy development has grown increasingly complex. There are now accelerated pathways for advanced therapy medicinal products (ATMPs) in several countries worldwide, including the U.S., Japan, and South Korea. While the possibility for accelerated commercialization has resulted from these changes, substantial complexity has also been introduced, making it a more elaborate process to move cell therapy products from bench to bedside.

In the interview with Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics, we get an experts perspective on how the regulatory environment has changed and new opportunities that exist for bringing cell therapy products through the clinical trial process and into the global marketplace.

Yaron Ramati: I have 10 years of experience in regulatory affairs in biotechnology companies in Israel.

I have a PhD in Philosophy of Biology from the London School of Economics and an M.Sc. from the Technion in Neurobiology

Yaron Ramati:The United States, Japan, and South Korea are countries that have accelerated pathways that are unique for cell and gene therapies. Legislation took effect in Japan in late 2014, in South Korea in 2016, and in the United States in 2017.

Additionally, the EU has a program for product acceleration the Adaptive Pathways. Although it is not explicitly for cell and gene therapies, these have been given a lot of attention by the group.

Yaron Ramati:

In the United States: Regenerative medicine advanced therapy (RMAT) designation.Cell therapies that aim to treat serious medical conditions with high unmet need, and have preliminary favorable clinical data, can get the designation. It allows for accelerated approval (i.e., the use of biomarkers and intermediate endpoints for BLA, priority review).

In Japan: Conditional time-limited marketing authorization.This program allows for regenerative therapies (cell, gene and tissue therapies) to receive conditional marketing authorization for up to 7 years, following confirmation of safety and an initial proof of efficacy in Japan in diseases that are serious and have a high unmet need.

In South Korea: Conditional marketing authorization for cell therapy.As in Japan, this program allows for cell therapies to receive conditional marketing authorization for a limited time, following an initial proof of efficacy in serious diseases.

In EU: Adaptive Pathways pilot program. This program is a pilot program established by the EMA to explore ways in which the EMA can assist the streamlining the development of new promising therapies for serious conditions with high unmet need. Although this program is not explicitly for cell or gene therapy, it is the main focus of the group.

Yaron Ramati: All EU countries have a joint definition for ATMPs as set by EU regulation. Other countries have separate definitions that only partially overlap.

Yaron Ramati: Only few countries in the world are willing to be the first to provide marketing authorization for novel therapies. For ATMPs, European regulation does not allow individual countries in the union to provide marketing authorization, and so the EMA is the only gateway for ATMPs in Europe.

The U.S. FDA, Japan PMDA, and South Korea KFDA are the only others that are willing to be first to approve ATMPs.

Yaron Ramati: Currently, the EMA and PMDA are leading with four marketing approvals of cell and gene therapies each. RMAT designation procedure in the U.S. is expecting to give a boost to the products that are being developed for the U.S. market.

Yaron Ramati: Pluristem is very active in the field of accelerated development of its products. PLX-PAD of Pluristem has been accepted to the Japan conditional time-limited marketing authorization scheme by PMD, as well as to the adaptive pathways program of the EMA. It is active in both programs.

In addition, Pluristem intends to make use of the accelerated pathways offered for regenerative therapies in both the U.S. and in South Korea.

Yaron Ramati: The focus of Pluristem in these programs is the advancement of PLX-PAD. Pluristem had achieved understandings with EMA and PMDA regarding the accelerated approval of PLX-PAD for the treatment of critical limb ischemia (CLI).

It is the intention of Pluristem to achieve similar understandings with FDA, EMA, PMDA and KFDA regarding the development of PLX-PAD for the treatment of patients following hip fractures.

Yaron Ramati: PLX-PAD was accepted into the EMA adaptive pathways pilot program in 2015. Since then, Pluristem has taken advantage of this program in coming to an understanding with the EMA on the desired regulatory path of PLX-PAD in CLI. In addition, Pluristem undertook parallel scientific advice with the EMA and leading health technology assessment (HTA) bodies in Europe.

In this meeting, Pluristem received valuable feedback on the expectations that these bodies have for purposes of reimbursement in Europe. Pluristem has designed the Phase 3 PACE study in CLI patients in view of the feedback received from both the EMA and the HTA bodies, with the purpose of addressing their respective expectations.

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An Experts Perspective on Accelerated Pathways for Cell ...

IPS Cell Therapy Comments Off on An Experts Perspective on Accelerated Pathways for Cell … | August 20th, 2017

On Monday, a group of scientists at Cedars-Sinai Heart Institute in Los Angeles, CA, discovered througha world-first experimenta form to rejuvenate elder rats old hearts by injecting cardiac stem cells from much younger rats with healthier hearts. They hope this process might eventually become useful to humans.

The first time an experiment like this was carried out was in 2009 by the same Los Angeles-based team. Now, they also proved the possibility of reversing aging in old hearts.

Heart failure is a typical cause of death in humans. Around 48 percent of women and 46 percent of men die a year from heart attacks and other heart-related diseases. They are the first reason of death worldwide, and a leading cause of death in the United States, killing over 375,000 Americans a year. Nearly half of all African-American population suffers from heart diseases.

Researchers took stem cells from the hearts of 4-month-old rats, shaped them into cardiosphere-derived cells and injected them into the hearts of other rats of 22 monthsold, an age that makes them be considered as old. They carried out a similar process to another group of rats but injected saline instead. Scientists later compared both groups.

After receiving the stem cells injection, researchers noted a significant change in the way old rats continued to live. They turned much more active and improved their functionalities. Not just their heart rates got better and faster, but also the way they ran and breathed. Their hair started to grow faster, their chromosomal telomeres which commonly shrink with age lengthened, plus other benefits. The rodents began to progressively improve their capacity of exercise along with their stamina overall.

The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because Im kind of losing my hair) the animals regrew their fur a lot better after theyd gotten cells compared with the placebo rats, said Dr Eduardo Marbn, director of the Cedars-Sinai Heart Institute and lead author, who is also extremely excited for having witnessed the unexpected fountain of youth.

In 2009, his team successfully repaired the damaged heart of a man who had suffered a heart attack, using his own heart tissue.

Stem cells are a really basic type of cells that can be molded and converted into other much-specialized cells through a process called differentiation, which is basicallyshaping them into any kind of body cell.They form in embryos like embryonic stem cells -, which help in the growth process of babies, along with the millions of other different cell types they need before their birth.

One of many cells scientists generated from stem cells is called progenitor cell, which shares some of the same properties. But unlike the original cells, progenitor cells are not able to divide and reproduce indefinitely. Dr. Marbn also said they discovered cardiosphere-derived cells, which tend to promote the healing of a condition that affects more than 50 percent of patients suffering from heart failure.

Our previous lab studies and human clinical trials have shown promise in treating heart failure using cardiac stem cell infusions, said Dr Marbn. Now we find that these specialized stem cells could turn out to reverse problems associated with aging of the heart.

According to Dr. Marbn, stem cells secrete exosomes, tiny vesicles which contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injuries, and the way genes are expressed in the tissue. They are placed into the heart, and act to transform it into a better organ, helping it at the same time to improve exercise capacity and hair regrowth, he explained.

Now, Dr. Marbn is exploring a much easier way to deliver the stem cells intravenously, instead of injecting them directly into the heart. Thus avoiding surgeries, which tend to be more complicated and expensive for the patient.

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

Now, scientistsneed to make more extensive studies before using the technique in humans.

Source: CNN

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Scientists discovered how to rejuvenate rats by injecting stem cells ... - Pulse Headlines

Cardiac Stem Cells Comments Off on Scientists discovered how to rejuvenate rats by injecting stem cells … – Pulse Headlines | August 19th, 2017

New research funded by the National Institutes of Health used 3-D collections of brain tissue grown from human cells to study the brains star-shaped astrocytes. (Image credit: Sergiu Pasca, Stanford University)

BETHESDA, Md. (CN) Its been two years since Stanford neurobiologists published a method for converting adult skin cells into induced pluripotent stem cells that could then be grown into 3-D clusters of brain cells.

The National Institutes of Health reported Wednesday that another crop of scientists have been studying the growth of star-shaped brain cells known as human cortical spheroids (hCSs) in these cell clusters.

Their findings, published in Neuron, confirm that the maturation of lab-grown cells largely mimics that of cells taken directly from brain tissue during very early life, a critical time for brain growth.

Because of the critical role this process plays in normal brain development, further study of lab-grown hCSs could uncover the underlying developmental biology at the core of various neurological and mental health disorders, such as schizophrenia and autism.

The hCS system makes it possible to replay astrocyte development from any patient, said Ben Barres, a Stanford professor of neurobiology who co-led the 2015 study, as quoted the NIH in a Wednesday article.

Thats huge, Barres added. Theres no other way one could ever do that without this method.

Steven Sloan, a student in Stanfords MD/Ph.D. program, led the astrocyte-comparison study published in the latest issue of Neuron.

The team grew the hCSs for 20 months, one of the longest-ever studies of lab-grown human brain cells, according to the report by the NIH, which funded the research in part through its National Institute of Neurological Disorders and Stroke.

Jill Morris, who directs the NINDS, said the work by Sloans team addresses a significant gap in human brain research by providing an invaluable technique to investigate the role of astrocytes in both normal development and disease.

David Panchision, program director at the National Institute of Mental Health, which also helped fund the study, also spoke to the studys importance.

Since astrocytes make up a greater proportion of brain cells in humans than in other species, it may reflect a greater need for astrocytes in normal human brain function, with more significant consequences when they dont work correctly, Panchision added.

One point that the researchers emphasized, however, is that hCSs are only a model and lack many features of real brains.

Moreover, certain genes that are active in fully mature astrocytes never switched on in the hCS-grown astrocytes, which they could conceivably do if the cells had more time to develop, the NIH article says. To address this question, the researchers now hope to identify ways to produce mature brain cells more quickly. hCSs could also be used to scrutinize precisely what causes astrocytes to change over time and to screen drugs that might correct any differences that occur in brain disease.

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New Cell Study Pulls Curtain on Schizophrenia, Autism - Courthouse News Service

Skin Stem Cells Comments Off on New Cell Study Pulls Curtain on Schizophrenia, Autism – Courthouse News Service | August 16th, 2017

New research reveals that a low-calorie diet rejuvenates the biological clock in a powerful manner, keeping the body younger.

Scientists have determined that a diet low in calories facilitates the energy-regulating processes. A low-calorie diet also helps to keep the body younger. These results were recently outlined in Cell. The finding is attributable to scientists at the University of California at Irvine's Center for Epigenetics and Metabolism. The team of scientists has revealed the manner in which the body's circadian rhythms alter due to the aging process. These rhythms are the body's biological clock. The circuit controlled by the clock directly connectedto aging is centered on the efficient metabolism of energy in cells.

About the Study

The group of scientists used mice for their study. These mice were tested at six months and at 18 months of age. Tissue samples were taken from their livers. This isthe organ that serves as the interface between food intake and energy distribution within the body. Energy is metabolized in cells in accordance with nuanced circadian controls.

Findings

The scientists determined the 24-hour cycle of the older mice's metabolic systems stayed the same. There were significant changes in the circadian mechanism that triggers genes on and off according to the usage of energy within cells. This means older cells process energy in an inefficient manner. The mechanism works quite well in young mice but shuts off in older mice.

A second group of older mice was provided with a diet containing 30 percent fewer calories. This intake period lasted half a year. Energy processing in the cells ended up more than unchanged. Caloric restriction functions through a rejuvenation of the biological clock. Inthe context of the study, good aging is the result of a good clock.

Collaboration for Confirmation

A companion study outlined in Cell explains the work performed by a group of researchers from the Barcelona Institute for Research in Biomedicine. These researchers collaborated with the team described above to gauge body clock functionality in stem cells from the muscle and skin of young and old mice. They determined a diet low in calories conserved the majority of rhythmic functions that occur during youth. This is the additional proof needed to show a low-calorie diet significantly contributes to the prevention of the aging process's effects. It is important to keep the stem cells' rhythm young as these cells will function to renew and preserve day-night tissue cycles.

Consuming less food seems to ward off tissue aging. As a result, stem cells do notreprogram circadian activities. Thestudies described above are important as they help explain why low-calorie diets slow aging in mice. The same results might hold true for human beings.

The Study's Importance

Prior fruit fly studies have shown diets low in calories boost longevity. However, the research described above is the first to show caloric restriction impacts circadian rhythms' impact on cell aging. These studies reveal the cell path through which the aging process is controlled. The findings serve as an introduction as to how the elements of aging can be controlled in terms of pharmacology.

What's Next?

The scientists involved in these studies are adamant it is necessary to continue examining why metabolism produces a dominant effect on stem cell aging. When the link that delays or promotes aging has been pinpointed, treatments must be developed to regulate the link.

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A Low-Calorie Diet Slows Aging - Anti Aging News

Skin Stem Cells Comments Off on A Low-Calorie Diet Slows Aging – Anti Aging News | August 15th, 2017