From left to right: Richard Stone, a doctor at Dana-Farber Cancer Institute in Boston, poses with Peter Karalekas (center), 76, and Matthew Churitch, 22. Churitch donated stem cells to Karalekas two years ago, and he visited Dana-Farber with Karalekas earlier this summer. (Courtesy photo)

BOSTON -- After winding his way through Massachusetts, Connecticut, New Hampshire and Maine for 76 years, Peter Karalekas has a proclamation: He's a Southerner now.

He still lives in Kittery, Maine, just about an hour from the Lowell middle school where he taught for 21 years.

He has no plans to move.

Rather, Karalekas considers himself a Southerner because of his stem cells.

He never exactly felt all that sick.

Karalekas worked tirelessly for decades, first as a teacher and coach at the James S. Daley Middle School in Lowell and then as the owner of a half-dozen T-Bones restaurants across New Hampshire.

Even despite the 12-hour days, seven days a week, in the grind of the restaurant industry, Karalekas felt healthy and rarely fell ill.

Peter Karalekas, left, a 76-year-old former Lowellian, smiles during his first meeting with Matthew Churitch, 22, of Nashville, Tennessee, who helped save Karalekas life by donating stem cells. (Courtesy photo)

The two, who do not have children, moved to Kittery 17 years ago.

Everything started to change in 2014.

Karalekas recalls being "short-winded," but he had very few other symptoms when he was diagnosed with myelodysplastic syndrome, a rare type of cancer in which the bone marrow is damaged and cannot produce enough blood cells.

The prognosis was not good.

"They said the only thing that would save me was a stem cell transplant," Karalekas said. "Otherwise, I had a couple of months to live, because my cells were all dropping drastically.

He went onto a registry, hoping for a donor to pop up, but doctors told him it could take from six months to two years to find the right match. Even with a transplant, Karalekas said, his chances of success were "30 to 40 percent."

The call came four weeks later.

Matthew Churitch got his call quickly, too.

He joined the National Marrow Donor Program's Be the Match Registry in 2014, the summer between his freshman and sophomore years at Clemson University. His mother had been on the registry to donate for years. Churitch's decision was simple: When a friend was diagnosed with leukemia, he knew he should sign up, too.

He did the requisite cheek swab, unsure if he would ever even be contacted to donate. By the time he had finished the following semester, he got the call.

A match was found.

Churitch went through several more levels of testing and preparation to donate stem cells to a stranger. He went to Clemson's student health center to have blood drawn.

He returned to his native Nashville, Tennessee, going to a medical center 10 days in a row to receive shots in his stomach that would stimulate his bone marrow and prepare his cells for transplant.

He sat for eight hours, a needle in each arm as his stem cells were filtered out so they could be transferred to Boston.

"Getting the shots isn't fun," he said. "You're pretty sore afterward for a few weeks. But knowing that the person on the other end is in hundreds and hundreds times more pain than any donor would ever go through -- that kind of pushed me through."

Karalekas and Churitch first connected via an anonymous letter, per the transplant registry's rules, updating Churitch on Karalekas's lengthy, isolated recovery. They were able to speak directly after a year.

Churitch dialed Karalekas' number on a lengthy walk to class, took a deep breath and hit the call button. Moments later, both men were crying and laughing.

"That was really awesome, just being able to hear his voice and recognize that there's somebody else on the other end of this," Churitch said. "A lot of people don't get the chance to connect with their recipients or their donors."

Karalekas wanted more. He told his wife early on that he wanted to meet his "angel from heaven," so when Churitch graduated Clemson earlier this year, Karalekas paid to bring the 22-year-old and his mother to New England.

In late June, Karalekas and his wife pulled into a pickup lane at Logan International Airport in Boston.

"I got out of the car, I charged over, and I gave them both a huge hug," Karalekas said.

Karalekas showed Churitch and his mother around for five days.They went on a private tour of Fenway Park; they wandered the historic streets of Portsmouth, New Hampshire; they visited Dana-Farber together to meet the team that treated Karalekas.

Both families quickly bonded. Karalekas recalls his brother George asking Churitch about his portable phone charger, expressing curiosity about how convenient it was. A few weeks later, a brand-new portable charger arrived at George's door, a gift from Churitch.

In January, Karalekas and his wife will vacation in Arizona and will cheer on Churitch's mother -- without Churitch even present -- in the Phoenix Marathon.

Donor and recipient talk every week.

"It's like we're a very, very close-knit family now," Karalekas said. "He's the son we never had."

Churitch is now in his first year at the University of South Carolina School of Medicine Greenville with hopes of becoming a physician. He hopes to use Karalekas's experience as inspiration for any patients facing future hardship, and he hopes that others, especially young people, will see their success and join the registry.

"You never know where that will take you," he said. "You can gain a friend for life, impact somebody and their family in need."

Karalekas said he feels he has a new life: His chances of beating the disease are now 97 percent, he says, up from the 30 percent or 40 percent when he started treatment. Thanks to the transplant from a handsome, athletic college student in Tennessee.

"I said, 'I'm a Southerner now,'" Karalekas said. "My stem cells are 99 percent this gentleman. I'm 99 percent him."

Follow Chris on Twitter @ChrisLisinski.

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For Lowell native, stem cell match becomes a match as friends - Lowell Sun

Bone Marrow Stem Cells Comments Off on For Lowell native, stem cell match becomes a match as friends – Lowell Sun | August 31st, 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

A team of scientists found a way to create a novel drug delivery system for an array of different conditions.

Researchers at the Fred Hutchinson Cancer Research Center developed a biomedical tool that harnesses nanoparticles to deliver transient gene changes to specified cells.

This system extends the therapeutic potential of messenger RNA (mRNA). This biological element is responsible for delivering molecular instructions from DNA to other cells in the body making them produce proteins to prevent or attack a disease.

The technique involves mixing freeze-dried nanoparticles with water and a sample of cells.

"Our goal is to streamline the manufacture of cell-based therapies," said lead author and biomaterials expert Dr. Matthias Stephan, a faculty member in the Fred Hutch Clinical Research Division, in a statement. "In this study, we created a product where you just add it to cultured cells and that's it -- no additional manufacturing steps."

Heres how this technology worked in three experiments targeting T-cells in the immune system and blood stem cells in a process they called hit-and-run genetic programming.

The team imbued these nanoparticles with a gene editing tool and sent them to T-cells residing in the immune system to snip out their natural T-cell receptors. They were then paired with genes encoding a CAR, otherwise known as a chimeric antigen receptor, designed to attack cancer.

Next, the researchers engineered the nanoparticles to target blood stem cells. They were equipped with mRNA that enabled the stem cells to multiply and replace blood cancer cells with healthy cells when used in bone marrow transplants.

Finally, the nanoparticles were targeted to CAR-T cells containing foxo1 mRNA that signaled to the anti-cancer T-cells to develop into a form of memory cell that exhibits more aggressive behavior and destroys tumor cells more effectively.

Other attempts to engineer the mRNA into disease-fighting cells were more difficult. The large messenger molecules degraded quickly before it could make it have an effect while the bodys immune system recognized it as foreign.

Still, this process could replace the more labor-intensive alternative called electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms.

Stephan is currently looking for commercial partners to help move into clinical trials.

The study was published in the journal Nature Communications.

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Nanoparticle Advance Could Yield Multi-Purpose Treatments - Drug Discovery & Development

Bone Marrow Stem Cells Comments Off on Nanoparticle Advance Could Yield Multi-Purpose Treatments – Drug Discovery & Development | 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

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.

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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)

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Bone Marrow Stem Cells Comments Off on In Osteoporosis, differentiation of mesenchymal stem cells … | August 30th, 2017

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

Bone Marrow Stem Cells Comments Off on Frawley, Mindell/Brody, Calkins Awards Recognize 5 for Excellence – UB School of Medicine and Biomedical Sciences News | August 30th, 2017

Essentially, nanoparticles carried a gene-editing tool to T cells of the immune system that snipped out their natural T-cell receptors, and then was paired with genes encoding a chimeric antigen receptor, or CAR, a synthetic molecule designed to attack cancer.

Next, nanoparticles were targeted to blood stem cells and equipped with mRNA that enabled the stem cells to multiply and replace blood cancer cells with healthy cells when used in bone marrow transplants.

Finally, nanoparticles were targeted to CAR T cells and equipped with Foxo1 mRNA, which signals the anticancer T cells to develop into a type of "memory" cell that is more aggressive and destroys tumor cells more effectively and maintains antitumor activity longer.

"Our goal is to streamline the manufacture of cell-based therapies," said lead author Matthias Stephan, M.D., Ph.D., a faculty member in the Fred Hutch Clinical Research Division and an expert in developing biomaterials. "In this study, we created a product where you just add it to cultured cells and that's itno additional manufacturing steps."

Dr. Stephan and his colleagues developed a nanoparticle delivery system to extend the therapeutic potential of mRNA, which delivers molecular instructions from DNA to cells in the body, directing them to make proteins to prevent or fight disease.

The researchers' approach was designed to zero in on specific cell typesT cells of the immune system and blood stem cellsand deliver mRNA directly to the cells, triggering short-term gene expression. It's called "hit-and-run" genetic programming because the transient effect of mRNA does not change the DNA, but it is enough to make a permanent impact on the cells' therapeutic potential.

Other attempts to engineer mRNA into disease-fighting cells have been tricky. The large messenger molecule degrades quickly before it can have an effect, and the body's immune system recognizes it as foreignnot coming from DNA in the nucleus of the celland destroys it.

Stephan and his Fred Hutch collaborators devised a workaround to those hurdles.

"We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation," Dr. Stephan explained. The researchers surrounded the nanoparticle with a negatively charged envelope with a targeting ligand attached to the surface so that the particle selectively homes in and binds to a particular cell type.

The cells swallow up the tiny carrier, which can be loaded with different types of man-made mRNA. "If you know from the scientific literature that a signaling pathway works in synergy, you could co-deliver mRNA in a single nanoparticle," Dr. Stephan elaborated. "Every cell that takes up the nanoparticle can express both."

The approach involves mixing the freeze-dried nanoparticles with water and a sample of cells. Within four hours, cells start showing signs that the editing has taken effect. Boosters can be given if needed. Made from a dissolving biomaterial, the nanoparticles are removed from the body like other cell waste.

"Just add water to our freeze-dried product," Dr. Stephan emphasized. Since it's built on existing technologies and doesn't require knowledge of nanotechnology, he intends for it to be an off-the-shelf way for cell-therapy engineers to develop new approaches to treating a variety of diseases.

The approach could replace labor-intensive electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. All the handling ends up destroying many of the cells, which limits the amount that can be used in treatments for patients.

Gentler to cells, the nanoparticle system developed by the Fred Hutch team showed that up to 60 times more cells survive the process compared with electroporation. This is a critical feature for ensuring enough cells are viable when transferred to patients.

"You can imagine taking the nanoparticles and injecting them into a patient; then you don't have to culture cells at all anymore," he asserted.

Dr. Stephan has tested the technology in cultured cells in the lab, but it's not yet available as a treatment. He is looking for commercial partners to move the technology toward additional applications and into clinical trials where it could be developed into a therapy.

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Cell Therapy Can Be Fast and Easy: Just Add mRNA Nanocarriers - Genetic Engineering & Biotechnology News

Bone Marrow Stem Cells Comments Off on Cell Therapy Can Be Fast and Easy: Just Add mRNA Nanocarriers – Genetic Engineering & Biotechnology News | August 30th, 2017

A diagram of a scaffold loaded with CAR T cells and microspheres containing nutrients to help the cells multiply and then leave the scaffold to go attack cancer cells. Credit: Cognition Studio, courtesy of Fred Hutchinson Cancer Research Center.

A new biomedical tool using nanoparticles that deliver transient gene changes to targeted cells could make therapies for a variety of diseasesincluding cancer, diabetes and HIVfaster and cheaper to develop, and more customizable.

The tool, developed by researchers at Fred Hutchinson Cancer Research Center and tested in preclinical models, is described in a paper published August 30 in Nature Communications.

"Our goal is to streamline the manufacture of cell-based therapies," said lead author Dr. Matthias Stephan, a faculty member in the Fred Hutch Clinical Research Division and an expert in developing biomaterials. "In this study, we created a product where you just add it to cultured cells and that's itno additional manufacturing steps."

Stephan and his colleagues developed a nanoparticle delivery system to extend the therapeutic potential of messenger RNA, which delivers molecular instructions from DNA to cells in the body, directing them to make proteins to prevent or fight disease.

The researchers' approach was designed to zero in on specific cell typesT cells of the immune system and blood stem cellsand deliver mRNA directly to the cells, triggering short-term gene expression. It's called "hit-and-run" genetic programming because the transient effect of mRNA does not change the DNA, but it is enough to make a permanent impact on the cells' therapeutic potential.

Stephan and colleagues used three examples to demonstrate their technology:

Other attempts to engineer mRNA into disease-fighting cells have been tricky. The large messenger molecule degrades quickly before it can have an effect, and the body's immune system recognizes it as foreignnot coming from DNA in the nucleus of the celland destroys it.

Stephan and his Fred Hutch collaborators devised a workaround to those hurdles.

"We developed a nanocarrier that binds and condenses synthetic mRNA and protects it from degradation," Stephan said. The researchers surrounded the nanoparticle with a negatively charged envelope with a targeting ligand attached to the surface so that the particle selectively homes in and binds to a particular cell type.

The cells swallow up the tiny carrier, which can be loaded with different types of manmade mRNA. "If you know from the scientific literature that a signaling pathway works in synergy, you could co-deliver mRNA in a single nanoparticle," Stephan said. "Every cell that takes up the nanoparticle can express both."

The approach involves mixing the freeze-dried nanoparticles with water and a sample of cells. Within four hours, cells start showing signs that the editing has taken effect. Boosters can be given if needed. Made from a dissolving biomaterial, the nanoparticles are removed from the body like other cell waste.

"Just add water to our freeze-dried product," Stephan said. Since it's built on existing technologies and doesn't require knowledge of nanotechnology, he intends for it to be an off-the-shelf way for cell-therapy engineers to develop new approaches to treating a variety of diseases.

The approach could replace labor-intensive electroporation, a multistep cell-manufacturing technique that requires specialized equipment and clean rooms. All the handling ends up destroying many of the cells, which limits the amount that can be used in treatments for patients.

Gentler to cells, the nanoparticle system developed by the Fred Hutch team showed that up to 60 times more cells survive the process compared with electroporation. This is a critical feature for ensuring enough cells are viable when transferred to patients.

"You can imagine taking the nanoparticles, injecting them into a patient and then you don't have to culture cells at all anymore," he said.

Stephan has tested the technology is cultured cells in the lab, and it's not yet available as a treatment. Stephan is looking for commercial partners to move the technology toward additional applications and into clinical trials where it could be developed into a therapy.

Explore further: Implanted scaffold with T cells rapidly shrinks tumors

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Nanoparticles loaded with mRNA give disease-fighting properties to cells - Medical Xpress

Bone Marrow Stem Cells Comments Off on Nanoparticles loaded with mRNA give disease-fighting properties to cells – Medical Xpress | August 30th, 2017

A new review looks at the potential of fetal membranes, which make up the amniotic sac surrounding the fetus during pregnancy, for regenerative medicine.

Fetal membranes have been used as biological bandages for skin grafts as well as for serious burns. They may also have numerous other applications because they contain a variety of stem cells, which might be used to treat cardiovascular and neurological diseases, diabetes, and other medical conditions.

"The fetal membranes have been used successfully in medical applications for over a century, but we continue to discover new properties of these membranes," said Dr. Rebecca Lim, author of the STEM CELLS Translational Medicine review. "The stem cell populations arising from the fetal membranes are plentiful and diverse, while the membrane itself serves as a unique biocompatible scaffold for bioengineering applications."

Explore further: Stem cell research could prevent premature births

More information: Rebecca Lim. Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog?, STEM CELLS Translational Medicine (2017). DOI: 10.1002/sctm.16-0447

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Fetal membranes may help transform regenerative medicine - Medical Xpress

Bone Marrow Stem Cells Comments Off on Fetal membranes may help transform regenerative medicine – Medical Xpress | August 30th, 2017

Dr. Khan from Wasatch Pain Solutions gave us insight to Regenexx, the world's most advanced stem cell and blood platelet procedures.

On what makesRegenexx treatments better than any other, Dr. Khan explained that a network of doctors and researchers have performed more stem cell related procedures than any other group in the United States; over 51,000 procedures. Which he says has lead them to producing over 50% of all available orthopedic stem cell research in the world.

Dr. Khan explained they only use a persons own living stem cells from their bone marrow along with their own blood platelets during their patented 3-step process. Studies show that bone marrow stem cells are vastly superior for orthopedic applications like helping to regenerate cartilage and heal tissue damage. The outcome that their process produces can help patients avoid surgery and maintain a very active lifestyle without severe pain.

For more information visit wasatchpainsolutions.com or call (801) 302-2690.

This story includes sponsored content.

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How your own stem cells could relieve your chronic pain - Good4Utah

Bone Marrow Stem Cells Comments Off on How your own stem cells could relieve your chronic pain – Good4Utah | August 29th, 2017

The U.S. Food and Drug Administration on Monday announced a crackdown on deceptive and dangerous stem cell clinics, starting with actions against a California company accused of giving smallpox vaccine to cancer patients, and a Florida company that ruined the eyesight of three women.

Our actions today should also be a warning to others who may be doing similar harm, FDA Commissioner Scott Gottlieb said in a statement, urging consumers and health-care providers to report rogue clinics and injuries.

FDA Commissioner Scott Gottlieb

The California company, San Diego-based StemImmune Inc., was combining the vaccine with stem cells derived from fat, then giving it intravenously or injecting it into tumors of cancer patients at clinics in Rancho Mirage and Beverly Hills, Calif., the FDA said.

U.S. marshals on Friday seized five vials of smallpox vaccine, including one that was partially used. The agency is investigating how the company obtained the vaccine, which has been stockpiled by the government in case of a bioterrorist attack.

The vaccine is made with live vaccinia virus, a poxvirus similar to but less harmful than smallpox. The vaccine could cause life-threatening problems in immune-compromised cancer patients, and alsoin certain unvaccinated people who might be accidentally infected by the patients, the FDA explained.

Speaking as a cancer survivor, Gottlieb said in a statement, I know all too well the fear and anxiety the diagnosis of cancer can have and how tempting it can be to believe the hollow claims made by these kinds of unscrupulous clinics. The FDA will not allow deceitful actors to take advantage of vulnerable patients.

In a separate enforcement action, the FDA sent a warning letter last week to U.S. Stem Cell Clinic of Sunrise, Fla., saying it could face product seizure or an injunction. Agency inspectors found that the clinic was processing fat-derived stem cells and claiming to treat a raft of conditions, including Parkinsons disease, amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, diabetes, and heart failure.

In March, U.S. Stem Cell made headlines when an article in the New England Journal of Medicine reported that three women with age-related macular degeneration suffered severe and permanent vision damage one was blinded after stem cells were injected into their eyeballs at the clinic. The article was written by doctors unconnected with the clinic who treated the women for the disastrous results.

Critics of unapproved stem cell treatments have called for tougher oversight by the FDA, as well as by the Federal Trade Commission, which regulates advertising, and by state medical boards, which oversee the practice of medicine.

The regulatory moves come as so-called regenerative medicine is exploding, spawning an industry built on unproven treatments using stem cells from bone marrow or fat. In recent months, networks of chiropractors have run big-budget ads for such treatments in newspaper across the country, including the Inquirer. Those ads, however, focus on addressing orthopedic problems such as degenerative discs and arthriticknees.

The only FDA-approved stem cell therapies involve using cells from bone marrow or umbilical cord blood to treat blood cancers and certain immune disorders. In general, biologic tissues that are processed and marketed as therapies are supposed to go through the FDAs drug approval process, which involves years of costly clinical testing in humans.

However, the FDA has tried to find a middle ground, recognizing the potential promise of stem cells in tissue repair and regeneration. The FDA has published, but has not finalized, draft guidance for stem cell products, saying they can be exempted from the drug approval process under certain scenarios. Among other criteria, the cells must be minimally manipulated and used in a homologous way, meaning for the same function they perform naturally in the body.

In a policy statement issued Monday, Gottlieb promised that this fall, the agency will advance a comprehensive policy framework that will more clearly describe the rules of the road for this new field. It will enable responsible product developers to gain FDAapproval with minimal burdens and costs.

We want to facilitate innovation, he wrote.

Published: August 28, 2017 4:42 PM EDT

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FDA moves to curb dangerous stem cell clinics - Philly.com

Bone Marrow Stem Cells Comments Off on FDA moves to curb dangerous stem cell clinics – Philly.com | August 29th, 2017

RENTON Turns out, Doug Baldwin started this current Seahawks fad of traveling outside the teams normal medical coverage to get far-flung treatment using body cells.

The Seahawks No. 1 wide receiver told me Monday he went overseas before this season -- to England, to be exact -- for pre-emptive, preventative treatment to maintain healthy knees.

I had mine in the offseason. I did stem-cell, Baldwin said, drenched in sweat in the hallway outside the teams locker room just after completing Mondays practice.

I mean, I dont have any ailments. Im trying to find every edge I can get.

Baldwin, Seattles $46 million receiver, tied Bobby Engrams 2007 franchise record with 94 receptions last season. He earned his first Pro Bowl selection. In 2015, the season that led to his contract extension, he co-led the NFL with 14 touchdown catches.

He said hed been looking into stem-cell therapy for years.

Transplanting or using bone marrow is the most widely used stem-cell therapy to treat or prevent a condition or disease. The U.S. Food and Drug Administration further explains stem cells may also help repair the body by dividing to replenish cells that are damaged by disease, injury, or normal wear.

So why London for Baldwin?

The FDA, as stated on its website, has not approved any stem cell-based products for use in this country other than using human umbilical cord blood forming stem cells for certain diseases.

There was a company wed be speaking to, Baldwin said of the London place he got treatment, without wanting to disclose many details. Did my research. Took my two years to finally decide.

In the last two weeks, seven Seahawks have gone away and outside the teams regular medical treatment to get a debated blood-re-injection process called regenokine to treat aching joints and/or aid in recovery from surgery. The treatment was founded in Germany, where its known as orthokine.

K.J. Wright returned last week from regenokine treatment, the re-injection of ones blood after it is heated and spun in a centrifuge to enhance its anti-inflammatory properties. The Pro Bowl outside linebacker played in Seattles exhibition last Friday against Kansas City.

D.J. Alexander the Pro Bowl special-teams player the Seahawks acquired this summer in a trade with Kansas City, went for regenokine treatment last week.

On Monday, coach Pete Carroll said wide receiver and kick returner Tyler Lockett, Pro Bowl defensive ends Michael Bennett and Cliff Avril, starting left guard Luke Joeckel and starting outside linebacker Michael Wilhoite are away from the team getting the same treatment Wright and Alexander had. Carroll said the team expects all those players to be ready for the opening game Sept. 10 at Green Bay.

That process reportedly costs $10,000. That doesnt count the travel and hotel costs of flying to get the therapy, of course. The FDA has yet to approve regenokine for use in the U.S., largely because its still unproven and reportedly because the agency has issues with the heating of the blood.

That is probably why Carroll said this on Thursday: Ive never had the OK that I can talk about it; I dont even know if I can talk about it. I was always afraid I wouldnt pronounce it right. But what I know its called is regenokine.

Dr. Peter Wehling in Germany, the man who founded the procedure known there as orthokine, was said in 2013 to have treated 30 to 40 NFL players with it. At that time the treatment process took four days, which could explain why Wright and his Seahawks successor have been missing a week of practices and games this month for it.

LifeSpan Medicine, clinic in Santa Monica, California, with offices also in New York and Dallas, lists regenokine as one the regenerative therapies it practices -- again, without FDA approval for use in this country.

Carroll said this on Monday:

Baldwin turns 29 next month. The opening at the Packers will begin the second season of the four-year, $46 million extension he signed in the summer of 2016. He looked ready for the 2017 season in Seattles most recent preseason game, Friday against Kansas City. He had two catches for 45 yards in 2 1/2 quarters, racing across the field and away from Chiefs defenders.

Hes only missed two games in his six-year career. Those absences were in his second season, 2012, after Seattle signed him as one of the leagues most successful undrafted free agents of the last decade.

Now, hes one of the trend-setters among eight Seahawks whove received alternative therapy.

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Trendsetter: Why Doug Baldwin went to England for stem-cell therapy - The News Tribune (blog)

Bone Marrow Stem Cells Comments Off on Trendsetter: Why Doug Baldwin went to England for stem-cell therapy – The News Tribune (blog) | August 29th, 2017

Bone marrow contains hematopoetic stem cells, the precursors to every blood cell type. These cells spring into action following bone marrow transplants, bone marrow injury and during systemic infection, creating new blood cells, including immune cells, in a process known as hematopoiesis.

A new study led by University of Pennsylvania and Technical University of Dresden scientists has identified an important regulator of this process, a protein called Del-1. Targeting it, the researchers noted, could be an effective way to improve stem cell transplants for both donors and recipients. There may also be ways to modulate levels of Del-1 in patients with certain blood cancers to enhance immune cell production. The findings are reported this week in The Journal of Clinical Investigation.

Because the hematopoetic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications, said George Hajishengallis, the Thomas W. Evans Centennial Professor in the Department of Microbiology in Penns School of Dental Medicine and a senior author on the work.

I think that Del-1 represents a major regulator of the hematopoetic stem cell niche, said Triantafyllos Chavakis, co-senior author on the study and a professor at the Technical University of Dresden. It will be worthwhile to study its expression in the context of hematopoetic malignancy.

For Hajishengallis, the route to studying Del-1 in the bone marrow began in his field of dental medicine. Working with Chavakis, he had identified Del-1 as a potential drug target for gum disease after finding that it prevents inflammatory cells from moving into the gums.

Both scientists and their labs had discovered that Del-1 was also expressed in the bone marrow and began following up to see what its function was there.

In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes [white blood cells] from the marrow into the periphery, Hajishengallis said, something analogous to what it was doing in the gingiva. But it turned out it had a much more important and global role than what I had imagined.

The researchers investigations revealed that Del-1 was expressed by at least three cell types in the bone marrow that support hematopoetic stem cells: endothelial cells, CAR cells and osteoblasts. Using mice deficient in Del-1, they found that the protein promotes proliferation and differentiation of hematopoetic stem cells, sending more of these progenitor cells down a path toward becoming myeloid cells, such as macrophages and neutrophils, rather than lymphocytes, such as T cells and B cells.

In bone marrow transplant experiments, the team discovered that the presence of Del-1 in recipient bone marrow is required for the transplanted stem cells to engraft in the recipient and to facilitate the process of myelopoesis, the production of myeloid cells.

When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to those with normal Del-1 levels.

We saw roles for Del-1 in both steady state and emergency conditions, Hajishengallis said.

Hajishengallis, Chavakis and their colleagues identified the protein on hematopoetic stem cells with which Del-1 interacts, the 3 integrin, perhaps pointing to a target for therapeutic interventions down the line.

The scientists see potential applications in bone marrow and stem cell transplants, for both donors and recipients. In donors, blocking the interaction between Del-1 and hematopoetic stem cells could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation. Transplant recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.

In addition, people undergoing chemotherapy who develop febrile neutropenia, associated with low levels of white blood cells, might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.

Its easy to think of practical applications for these findings, said Hajishengallis. Now we need to find out whether it works in practice, so our studies continue.

Ioannis Mitroulis, Lan-Sun Chen and Rashim Pal Singh of TU-Dresden were co-lead authors on the study, and Ben Wielockx of TU-Dresden was a co-senior author along with Hajishengallis and Chavakis. They were joined by coauthors Tetsuhiro Kajikawa, Kavita Hosur, Tomoki Maekawa and Baomei Wang of Penn Dental Medicine; Ioannis Kourtzelis, Matina Economopoulou, Maria Troullinaki, Athanasios Ziogas, Klara Ruppova, Pallavi Subramanian, Panayotis Verginis, Malte Wobus, Martin Bornhuser and Tatyana Grinenko of TU-Dresden; Torsten Tonn of the German Red Cross Blood Donation Service in Dresden; and Marianna Di Scala and Andrs Hidalgo of the Spanish National Center for Cardiovascular Research.

The study was supported by the Deutsche Forschungsgemeinschaft, European Commission, European Research Council and National Institutes of Health (grants AI068730, DE024153, DE024716, DE0152 54 and DE026152).

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Bone Marrow Protein May Be Target for Improving Stem Cell Transplants - Penn: Office of University Communications

Bone Marrow Stem Cells Comments Off on Bone Marrow Protein May Be Target for Improving Stem Cell Transplants – Penn: Office of University Communications | August 28th, 2017

PHOENIX, Aug. 28, 2017 /PRNewswire/ -- Creative Medical Technology Holdings Inc. (OTCQB ticker symbol CELZ) announced today completion of enrollment in the Company's clinical trial assessing safety and efficacy of its CaverstemTM procedure to treat erectile dysfunction in patients who do not respond to currently available treatments.Approximately 30% of the 30,000,000 patients suffering from erectile dysfunction do not respond to drugs like Viagra, Cialis and Levitra, in part due to an underlying degeneration of the biological machinery needed to achieve erections.

"The CaverstemTM procedure, which uses the patient's own bone marrow derived stem cells to induce arterial and venous regeneration, is an outpatient procedure able to be conducted by Urologists in their medical facilities. We are using a patient's own cells and we do not manipulate the stem cells through the use of chemicals, growth factors or expansion and have experienced no procedure-related safety issues," said Dr. Thomas Ichim Co-Founder and Chief Scientific Officer of Creative Medical Technology Holdings, Inc.

The clinical trial covering patients ages 18 to 80 received Institutional Review Board (IRB) approval in December 2016. The trial is sponsored by us based on our patented technology and is conducted by Dr. Jacob Rajfer, Principal Investigator and Los Angeles Biomedical Institute at Harbor UCLA Hospital in Torrance, CA.

"I am pleased with the expedience and efficiency at which enrollment was reached. As someone who regularly sees patients suffering from treatment non-responsive erectile dysfunction, I am excited to see the development of a novel approach to treating this condition using the patient's own natural regenerative processes," said Dr. Alexander Gershman, member of the Company's Scientific Advisory Board and Director of Institute of Advanced Urology at the Cedars-Sinai Medical Tower; Director of Urologic Laparoscopy in the Division of Urology, Harbor-UCLA Medical Center."

"We are very fortunate to work with the expert team at Los Angeles Biomedical Institute - UCLA/Harbor Hospital who have done an outstanding job with subject recruitment, screening, treatment and follow-up.We firmly believe that we are on schedule for commercialization of the Caverstem TM procedure through publication and presentation of trial results, marketing, licensing, training and sales in 2018," said Timothy Warbington, President and CEO of Creative Medical Technology Holdings Inc.

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a clinical stage biotechnology company currently trading on the OTCQB under the ticker symbol CELZ. For further information about the company go to http://www.creativemedicaltechnology.com. For more information on our CaverstemTM procedure please go to http://www.caverstem.com.

Forward-Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website at http://www.sec.gov.

View original content:http://www.prnewswire.com/news-releases/creative-medical-technology-holdings-achieves-100-patient-enrollment-in-caverstemtm-clinical-trial-for-stem-cell-treatment-of-erectile-dysfunction-300509805.html

SOURCE Creative Medical Technology Holdings, Inc.

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Creative Medical Technology Holdings Achieves 100% Patient Enrollment in CaverstemTM Clinical Trial for Stem Cell ... - Markets Insider

Bone Marrow Stem Cells Comments Off on Creative Medical Technology Holdings Achieves 100% Patient Enrollment in CaverstemTM Clinical Trial for Stem Cell … – Markets Insider | August 28th, 2017

For anyone diagnosed with cancer, Alzheimers or AIDS, perhaps the best hope for finding cures lies in their own bodies more specifically, in the cells traveling through their blood.

Scientists at major universities and pharmaceutical companies need more of those cells to do their cutting-edge medical research, and Folsoms StemExpress is leading the way nationwide. Company CEO Cate Dyer is trying to get out the word to potential donors that their blood is essential to this work.

StemExpress collects blood, bone marrow, plasma or cord blood at its centers and compensates donors for their time and discomfort. Then it processes their samples into a range of products, including many of the cells on your bodys healing team: white blood cells, stem cells, T cells and others that answer the call when the body confronts a disease or disability.

We really want to get out to people in Sacramento and the region that we need diseased donors at our sites, and thats everyone people who have an early-diagnosed cancer, people in treatment, theyre having radiation post-treatment and remission, from everything like AML, leukemia, lymphoma, all of the major cancer space, said Cate Dyer, the companys founder and CEO. But also, we have AIDS projects going on right now where we need AIDS-positive samples.

Its not just cancer or AIDS, though. Some researchers also use cells from the samples to study chronic diseases such as diabetes and high blood pressure or to study illnesses that have no cures such as Alzheimers or Parkinsons.

Researchers can take many paths when studying cells from different people, at different stages of a disease, said Dr. Michael Chez, a pediatric neurologist with Sutter in the Sacramento region. For example, researchers could develop screenings for early detection of a disease or genetic defect, or duplicate defective tissues to see how to repair what went wrong. Their findings might help to develop drugs or chemicals that will help to reverse or change the course of a disease. Already, scientists have begun harvesting stem cells, turning them into specific tissues and using them for replacement or repair.

To help potential donors understand the impact they can have on research, Dyer highlighted the work that StemExpress started doing seven years ago with San Diego-based Sequenom, a life-sciences company that was attempting to develop a less-invasive way to check for genetic defects in fetuses. At the time, doctors were using a needle, pushing through the wall of the abdomen and into the uterus to collect and test elements of the amniotic fluid to assess genetic abnormalities.

It was a procedure that frightened women not only because of concerns about their unborn babies but also because they feared that they might be one of the small percentage of women who suffered a major complication as a result of the amniocentesis.

Sequenom envisioned a test that, by contrast, would simply examine blood drawn from the expectant mother. To develop the test, Sequenoms researchers would have to isolate and study DNA strands for both expectant moms and their fetuses. By studying DNA from thousands of donors, the life sciences company was able to identify DNA mutations, deletions and alterations and develop a way to check for them in the blood rather than in amniotic fluid.

At the time, when I met (Sequenoms senior director of clinical operations) they were sourcing about 25 (blood) samples a week, just to give you a ballpark, Dyer said, and I asked him, Well, how long is it going to take you to meet all the (Food and Drug Administration) requirements needed, sourcing 25 samples a week? And, he was like, Five to six years to get all our projects together.

Dyer made it her priority to significantly speed up that development timeline by delivering 300 samples a week, a feat she said the company accomplished within 90 days. Along the way, Stem Express became the largest global supplier of maternal blood for research purposes.

If it takes six years for them to source all the samples and another year and a half to get that through the FDA, youre looking at an eight-year turnaround just to get that ... to a patient, Dyer said. If we can shorten that, which we did, to almost a year and a half and get that then to the FDA and back out to patients, weve just massively impacted patient health care.

Chez talks regularly with patients or the parents of patients who are impatient for better treatments or cures, he said, but the availability of donor blood, cells and DNA already has sped up the pace of development of new drugs, screenings or treatments, and that pace should continue to improve as the bank of samples grows.

What also excites Chez is that multiple researchers can benefit from the millions of cells extracted from a blood draw from a single patient. Think of what this means, he said, for orphan diseases those conditions that affect fewer than 200,000 U.S. residents, such as Lou Gehrigs, cystic fibrosis or muscular dystrophy. A physician might run into a patient with one of these conditions once every 10 years, he said, but a few people living with these illnesses now have the power to provide cells to foster research around the world.

Experts then can study how a disease manifests at the cellular level, design methods of treatment and test them on human tissue in the lab, Chez said. There may not be enough patients in any one place to design treatment studies, he said, so human tissues can expand statistical ways to study the safety and efficacy of treatments.

One patient could help a disease study in multiple places versus just being limited to one researcher at one university, Chez said. If you have multiple people doing the work, it just amplifies how quickly things get done and the statistical power of that type of research. This is exponentially changing the algorithm of how research will be done in disease.

Dyer said she is often asked: Could giving blood pose a health risk for people struggling with cancer or other diseases? Her answer: It depends on the patient. StemExpress puts each donor through health assessments to determine how much blood they can give. Some patients may only be able to give one tablespoon; others, as much as six tablespoons.

Patients receive $25-$50 for blood draws, fees that are set by an independent review board. The company has collection centers at 2210 E. Bidwell St. in Folsom, another in Arlington, Mass., and is working to open another center in San Diego.

Researchers are typically specific about the kinds of diseased blood they need and even the stage or progression, Dyer said, so StemExpress is working to expand its donor database to ensure it has a variety of the cells needed.

Want to support biomedical research?

StemExpress is seeking people willing to give blood, white blood cells and bone marrow. The company accepts donations from patients who are healthy or those struggling with chronic or terminal illnesses.

The company compensates donors, based on the time they spend and the invasiveness of the procedure. People who give blood receive $25-50, for instance, while marrow donors receive $250.

A review board, independent of StemExpress, sets the payments. To learn more or to make an appointment, visit http://www.stemexpressdonors.com or call 1-877-900-7836.

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Struggling with a chronic or life-threatening illness? Your blood can help research cures - Sacramento Bee

Bone Marrow Stem Cells Comments Off on Struggling with a chronic or life-threatening illness? Your blood can help research cures – Sacramento Bee | August 28th, 2017

Researchers are looking for ways eliminate the need for bone marrow donors altogether and instead use different types of cells derived from the patient in need of a transplant, says Dr Vladislav Sandler.

At the moment, people who develop leukaemia, lymphoma and otherblood diseases often need to undergo a hematopoietic stem cell transplantation (HSCT). This is because initial treatment of the disease (front-line therapy) often fails and the disease comes back.

Hematopoietic stem cells (HSC) are vital because they constantly regenerate the blood system giving rise (differentiating) into all types of blood cells such as red blood cells, white blood cells and platelets. Sometimes,patients get cells for the HSCT from close relatives (related allogeneic transplantation), who happen to be a match or by using donor data bases that can match them with strangers (unrelated allogeneic transplantation). The patients own HSC are wiped out with chemotherapy and replaced with donated blood-forming steam cells which create healthy new blood cells free from disease.

The patients own HSC are wiped out with chemotherapy and replaced with the donated blood-forming stem cells which createhealthy new blood cellsfree from disease.

Often, there is not a perfect match between a donor and a patient but physicians try and find the closest one possible. When a match is not perfect, a risk of rejection of the newly transplanted cells significantly grows. There are several teams of researchers trying to find a way to eliminate the need for bone marrow donors altogether and instead use different types of cells derived from the patient in need of a transplant.

This work, to directly reprogram the patients own cells to create hematopoietic stem cells, (from which all cellular blood components are derived) has been going on for some time and has had some success[1][2][3]. However, it is a very long and cumbersome process to produce HSC cells from a patients own cells and it looks like this may never be a practicable solution to the problem. We simply cant seem to be able to get the newly formed HSC cells to replicate into the sufficient number of cells needed to form a viable HSCT.

What I discovered when I was at Cornell University was that there is a small subset of postnatal hemogenic endothelial cells (Hu-PHEC) which survive in the liver and blood vessels of the umbilical cord and placenta into adulthood. It has been known for quite a while that in the fetus, similar cells produce first definitive HSC. It was accepted as a dogma that they either lose their ability to do this after birth or simply disappear. However, as it often happens in science, this was not entirely correct. Hu-PHEC can be isolated from postnatal tissues and made to generate HSCde-novo.

In animal experiments, we took purified and stimulated Hu-PHEC and transplanted them into immunocompromised mice.

What we found was that the transplanted cells did engraft and created a healthy new human blood system in the recipient mice. What seemed to happen was that by putting them back into circulation within the body reactivated their ability to produce HSC cells as they doin utero.

We dont yet understand the mechanism but we are working on this and we need to work out a way to get enough cells for human transplantation.

Development of Hu-PHEC technology would create an opportunity to get rid of bone marrow/HSC donations. We would no longer have to go to a donor or a family member, but simply harvest some of these special post-natal hemogenic endothelial cells from the patients own body.

Another area of our research has been to develop a conditioning product which helps eliminate the patients diseased HSC with minimal collateral damage to the rest of the body. At the moment, patients undergo a rather terrible process of preparation for a HSCT. It involves chemotherapy and radiation and can seriously harm various unrelated healthy cells. In some cases, patients do not survive the conditioning process. We have developed a type of immune therapy which is a bi-specific antibody that redirects patients own immune cells to only attack and kill HSC. It leaves other cells alone, so does not damage reproductive system. This should mean that men and women undergoing conditioning in advance of a bone marrow transplantion would not need to undergo fertility saving treatment (no need to freeze sperm or eggs). This bi-specific antibody, which is filed for a world-wide patent, is much less dangerous and detrimental to health than current treatment options. We have proved its effectiveness in animal trials, but we are now hoping to move on to Phase 1 clinical trials within the next two years.

[1]Sandler, V. M. et al. Reprogramming human endothelial cells to hematopoietic cells requires vascular induction. Nature 511, 312-318, doi:10.1038/nature13547 (2014).Validated in: Lis, R. et.al. Conversion of adult endothelium to immunocompetent hematopoietic stem cells. Nature Published online 17 May 2017, doi:10.1038/nature22326 (2017).

[2]Sandler V.M et al.Reprogramming of Embryonic Human Fibroblasts into Fetal Hematopoietic Progenitors by Fusion with Human Fetal Liver CD34+ Cells. PLoS ONE 6(4) 2011.

[3] Pereira C.F. et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell. 2013 Aug 1;13(2):205-18.

Vladislav Sandler is the co-founder of HemoGenyx LLC, a US preclinical stage biotechnology company launching innovative new treatments for blood diseases using blood-forming (hematopoietic) stem cell transplantation (HSCT) techniques.

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Eliminating the need for bone marrow donors - The Hippocratic Post (blog)

Bone Marrow Stem Cells Comments Off on Eliminating the need for bone marrow donors – The Hippocratic Post (blog) | August 28th, 2017

Multiple sclerosis sufferer Roy Palmer is about to embark on the next phase of his pioneering treatment.

But it comes with risks he is prepared to take in the hope it will cure the debilitating condition.

The 43-year-old father of two from Quedgeley is determined it will work. He was diagnosed with relapsing remitting MS but now has the secondary progressive form of the disease, which means it gets steadily worse.

He said: I fought for a year to get hematopoietic stem cell transplantation and many people told me I didnt fit the criteria but I didnt let that stop me.

Mr Palmer had a week of injections to draw the stem cells from his bone marrow.

He and his wife Helen travelled to Hammersmith Hospital in London where he was given a day of chemotherapy.

Mr Palmer lost his hair as a result and was left feeling sick and tired.

The stem cells have been frozen and will be reintroduced to his body after another aggressive course of chemotherapy.

It will be fed directly into a main artery in his chest before Mr Palmer spends the next four weeks in isolation.

He will start the treatment on September 18 his 24th wedding anniversary.

Mr Palmer said: Im not someone to sit around and feel sorry for myself.

If the treatment works then, oh my God, I couldnt begin to describe what it would mean to me.

He added: To be able to walk out of my front door would mean the world.

I know Im lucky to be able to get the treatment. Im worried, my immune system will be obliterated, but I have to give this everything. Im a fighter and determined to make this work.

Mr Palmers family back his decision to undergo HSCT treatment, although they worry about the effect it will have.

His 45-year-old wife said: When they give the chemotherapy it brings the body back down to zero.

It will stop any immune system and take some time for the body to start getting back to normal.

When Roys levels are up they will start to reintroduce the stem cells.

The MS Society website says HSCT aims to reset the immune system to stop it attacking the central nervous system.

It uses chemotherapy to remove the harmful immune cells and then rebuilds the immune system using haematopoietic stem cells found in bone marrow.

They can produce all the different cells in the blood.

Mrs Palmer said: Im happy for Roy to take that risk and to support him but it is a lethal dose of chemo.

The treatment can be done abroad and costs around 60,000. In the past we were considering that option but there is no aftercare.

The couples daughter Abi, 12, said: I feel a little scared for dad but okay. I cant remember him walking.

And 20-year-old son Jack said: Dad has been in a chair for about 10 years and to see him walk again would mean everything.

Just standing next to each other would mean the world.

Once the stem cells are back in Mr Palmers body the hope is he will make a full recovery and be free of MS,

He said: It will be great to not have to ask people to do things for me.

I do what I can but I dont like to hang around waiting.

I want people to know there is treatment and it can be a fight but Ive got to do this now.

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MS sufferer gets pioneering stem cell treatment - Gloucestershire Live

Bone Marrow Stem Cells Comments Off on MS sufferer gets pioneering stem cell treatment – Gloucestershire Live | August 28th, 2017

It will take you just a few hours to donate stems cells but it will save someones life as it is usually the last or the only resort for those suffering from blood cancer. Stem cells are undifferentiated biological cells that can grow into specialized cells. There are two types of stems cells, which are embryonic stem cells and adult stem cells. Embryonic stem cells are extracted from theblastocyst, which is a structure that contains cell mass that develops into an embryo. Adult stem cells are the undifferentiated cells that replenish the dying cells or repair the damaged cells. These adult stems cells are donated during the stem cell donation. Stems cells are transferred to the patient, where it differentiates into healthy specialized cells. (ALSO READMajor blood types and who can donate blood to whom).

Stem cell donation is voluntarily donating the stem cells produced by your body. It can be donated in two ways. The first method is called Peripheral blood stem cell (PBSC) donation while the other method is bone marrow donation. Bone marrow donation requires hospitalization. Bone marrow is collected from your pelvis by doctors under general anesthesia using a syringe. You may experience pain and bruise but you will recover within a week.

Peripheral blood stem cell donation is used by 90 percent of the people to donate stem cells. It is an easy and quick process to collect the blood-forming cells found in the circulating blood. This non-surgical process of collecting the stem cells is called apheresis.

You need to register to donate stem cell. Your cell sample from cheek is analyzed for HLA typing and when there is a requirement for stem cell with your HLA type, you will get a notification. A complete health check-up is carried out to ascertain that you are fit to donate the stems cells. Once the check up is done, you will be given an injection called GCSF (Granulocyte Colony Stimulating Factor)to increase the stem cell present in your blood. This injection will be administered for five days and on the fifth day, the stem cells are collected. A tiny tube will be inserted in your arm and this tube is connected to a machine that will collect the stem cells. Your blood will pass through the machine. This procedure usually takes about five hours. You may experience flu like symptoms after donating the stem cells but it will soon subside.

Your cells will be given to those suffering from blood cancer and it could save the life of that person.

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What is stem cell donation: How does peripheral blood stem cell collection work? - India.com

Bone Marrow Stem Cells Comments Off on What is stem cell donation: How does peripheral blood stem cell collection work? – India.com | August 27th, 2017

Min Ma,1,* Shilin Chen,1,* Zhuo Liu,1 Hailong Xie,2 Hongyu Deng,3 Song Shang,1 Xiaohong Wang,4 Man Xia,5 Chaohui Zuo1

1Department of Gastroduodenal and Pancreatic Surgery, Laboratory of Digestive Oncology, Hunan Cancer Institute, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 2Institute of Cancer Research, South China University, 3Department of Laboratory Medicine, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 4Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, 5Department of Gynecological Oncology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

*These authors contributed equally to this work

Abstract: Worldwide, gastric cancer (GC) is one of the deadliest malignant tumors of the digestive system. Moreover, microRNAs (miRNAs) of exosomes harbored within cancer cells have been determined to induce inflammatory conditions that accelerate tumor growth and metastasis. Interestingly, the oncogenic role of bone marrow mesenchymal stem cells (BM-MSCs) in the modulation of immunosuppression, tumor invasion, and metastasis was discovered to be partly mediated through the secretion of exosomes. In this article, high expression of miRNA-221 (miR-221) in exosomes of the peripheral blood was determined to be positively correlated with the poor clinical prognosis of GC, especially with respect to tumor, node, and metastases stage. Therefore, the expression of miR-221 in exosomes of the peripheral blood may be an important detection index for GC. Proliferation, migration, invasion, and adhesion to the matrix of GC BGC-823 and SGC-7901 cells were significantly enhanced by exosomes that originated from BM-MSCs that were transfected with miR-221 mimics. In conclusion, extracted exosomes from BM-MSCs transfected with miR-221 oligonucleotides can act as high-efficiency nanocarriers, which can provide sufficient miR-221 oligonucleotides to influence the tumor microenvironment and tumor aggressiveness effectively. Notably, the use of a miR-221 inhibitor with an excellent restraining effect in exosomes provides therapeutic potential for GC in future clinical medicine.

Keywords: exosomes, miR-221, BM-MSCs, gastric cancer, prognosis, oncogenic activity

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miRNA-221 of exosomes originating from bone marrow mesenchymal stem cells promotes oncogenic activity in gastric ... - Dove Medical Press

Bone Marrow Stem Cells Comments Off on miRNA-221 of exosomes originating from bone marrow mesenchymal stem cells promotes oncogenic activity in gastric … – Dove Medical Press | August 26th, 2017