Stem Cell Clinic

U-M researchers find new gene involved in blood-forming stem cells

By Stem Cell Medical Center

ANN ARBOR--Research led by the University of Michigan Life Sciences Institute has identified a gene critical to controlling the body's ability to create blood cells and immune cells from blood-forming stem cells--known as hematopoietic stem cells.

The findings, scheduled for online publication in the Journal of Clinical Investigation April 13, provide new insights into the underlying mechanics of how the body creates and maintains a healthy blood supply and immune system, both in normal conditions and in situations of stress--like the body experiences following a bone marrow transplant.

Along with helping scientists better understand the body's basic processes, the discovery opens new lines of inquiry about the Ash1l gene's potential role in cancers known to involve other members of the same gene family, like leukemia, or those where Ash1l might be highly expressed or mutated.

"It's vital to understand how the basic, underlying mechanisms function in a healthy individual if we want to try to develop interventions for when things go wrong," said study senior author Ivan Maillard, an associate research professor at the Life Sciences Institute, where his lab is located, and an associate professor in the Division of Hematology-Oncology at the U-M Medical School.

"Leukemia is a cancer of the body's blood-forming tissues, so it's an obvious place that we plan to look at next. If we find that Ash1l plays a role, then that would open up avenues to try to block or slow down its activity pharmacologically," he said.

Graduate students Morgan Jones and Jennifer Chase were the study's first authors.

Dysfunction of blood-forming stem cells is well known in illnesses like leukemia and bone marrow failure disorders. Blood-forming stem cells can also be destroyed by high doses of chemotherapy and radiation used to treat cancer. The replacement of these cells through bone marrow transplantation is the only widely established therapy involving stem cells in human patients.

But even in the absence of disease, blood cells require constant replacement--most blood cells last anywhere from a few days to a few months, depending on their type.

Over more than five years, Maillard and his collaborators identified a previously unknown but fundamental role played by the Ash1l gene in regulating the maintenance and self-renewal potential of these hematopoietic stem cells.

The Ash1l (Absent, small or homeotic 1-like) gene is part of a family of genes that includes MLL1 (Mixed Lineage Leukemia 1), a gene that is frequently mutated in patients who develop leukemia. The research found that both genes contribute to blood renewal; mild defects were seen in mice missing one or the other, but lacking both led to catastrophic deficiencies.

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U-M researchers find new gene involved in blood-forming stem cells

To fight nasty digestive bugs, scientists set out to build a better gut — using stem cells

By Stem Cell Medical Center

New $6.4M federal grant support will fuel the development of 'guts in a dish' to study interaction between cells & microbes in both health and disease

IMAGE:These HIO structures, each about the size of a BB and grown from stem cells, allow scientists to study the interaction between the cells of the gut lining and microbes... view more

Credit: University of Michigan Medical School

ANN ARBOR, Mich. -- If you got hit with any of the 'intestinal bugs' that went around this winter, you've felt the effects of infectious microbes on your digestive system.

But scientists don't fully understand what's going on in gut infections like that - or in far more serious ones that can kill. Many mysteries remain in the complex interaction between our own cells, the helpful bacteria that live inside us, and tiny invaders.

Now, a team of University of Michigan scientists will tackle that issue in a new way. Using human stem cells, they'll grow tiny "guts in a dish" in the laboratory and study how disease-causing bacteria and viruses affect the microbial ecosystem in our guts. The approach could lead to new treatments, and aid research on a wide range of diseases.

This work was started as part of the U-M Medical School's self-funded Host Microbiome Initiative and Center for Organogenesis, and the U-M Center for Gastrointestinal Research, funded by the National Institutes of Health. It also received funding from the U-M's MCubed initiative for interdisciplinary work.

Now, the project has received a $6.4 million boost with a new five-year NIH grant.

It will allow the U-M team to expand their effort to grow human intestinal organoids, or HIOs - tiny hollow spheres of cells into which they can inject a mix of bacteria. They'll work with researchers at other institutions, as part of the Novel, Alternative Model Systems for Enteric Diseases, or NAMSED, initiative sponsored by the NIH's National Institute of Allergy and Infectious Diseases.

Balls of cells become mini-guts

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To fight nasty digestive bugs, scientists set out to build a better gut -- using stem cells

Stem Cell Injection May Soon Reverse Vision Loss Caused By Age-Related Macular Degeneration

By Stem Cell Treatment

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Newswise LOS ANGELES (EMBARGOED UNTIL 7 A.M. EDT on APRIL 14, 2015) An injection of stem cells into the eye may soon slow or reverse the effects of early-stage age-related macular degeneration, according to new research from scientists at Cedars-Sinai. Currently, there is no treatment that slows the progression of the disease, which is the leading cause of vision loss in people over 65.

This is the first study to show preservation of vision after a single injection of adult-derived human cells into a rat model with age-related macular degeneration, said Shaomei Wang, MD, PhD, lead author of the study published in the journal STEM CELLS and a research scientist in the Eye Program at the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

The stem cell injection resulted in 130 days of preserved vision in laboratory rats, which roughly equates to 16 years in humans.

Age-related macular degeneration affects upward of 15 million Americans. It occurs when the small central portion of the retina, known as the macula, deteriorates. The retina is the light-sensing nerve tissue at the back of the eye. Macular degeneration may also be caused by environmental factors, aging and a genetic predisposition.

When animal models with macular degeneration were injected with induced neural progenitor stem cells, which derive from the more commonly known induced pluripotent stem cells, healthy cells began to migrate around the retina and formed a protective layer. This protective layer prevented ongoing degeneration of the vital retinal cells responsible for vision.

Cedars-Sinai researchers in the Induced Pluripotent Stem Cell (iPSC) Core, directed by Dhruv Sareen, PhD, with support from the David and Janet Polak Foundation Stem Cell Core Laboratory, first converted adult human skin cells into powerful induced pluripotent stem cells (iPSC), which can be expanded indefinitely and then made into any cell of the human body. In this study, these induced pluripotent stem cells were then directed toward a neural progenitor cell fate, known as induced neural progenitor stem cells, or iNPCs.

These induced neural progenitor stem cells are a novel source of adult-derived cells which should have powerful effects on slowing down vision loss associated with macular degeneration, said Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and contributing author to the study. Though additional pre-clinical data is needed, our institute is close to a time when we can offer adult stem cells as a promising source for personalized therapies for this and other human diseases.

Next steps include testing the efficacy and safety of the stem cell injection in preclinical animal studies to provide information for applying for an investigational new drug. From there, clinical trials will be designed to test potential benefit in patients with later-stage age-related macular degeneration.

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Stem Cell Injection May Soon Reverse Vision Loss Caused By Age-Related Macular Degeneration

Stem cell injection may soon reverse vision loss due to age-related macular degeneration

By Stem Cell Treatment

LOS ANGELES (EMBARGOED UNTIL 7 A.M. EDT on APRIL 14, 2015) - An injection of stem cells into the eye may soon slow or reverse the effects of early-stage age-related macular degeneration, according to new research from scientists at Cedars-Sinai. Currently, there is no treatment that slows the progression of the disease, which is the leading cause of vision loss in people over 65.

"This is the first study to show preservation of vision after a single injection of adult-derived human cells into a rat model with age-related macular degeneration," said Shaomei Wang, MD, PhD, lead author of the study published in the journal STEM CELLS and a research scientist in the Eye Program at the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

The stem cell injection resulted in 130 days of preserved vision in laboratory rats, which roughly equates to 16 years in humans.

Age-related macular degeneration affects upward of 15 million Americans. It occurs when the small central portion of the retina, known as the macula, deteriorates. The retina is the light-sensing nerve tissue at the back of the eye. Macular degeneration may also be caused by environmental factors, aging and a genetic predisposition.

When animal models with macular degeneration were injected with induced neural progenitor stem cells, which derive from the more commonly known induced pluripotent stem cells, healthy cells began to migrate around the retina and formed a protective layer. This protective layer prevented ongoing degeneration of the vital retinal cells responsible for vision.

Cedars-Sinai researchers in the Induced Pluripotent Stem Cell (iPSC) Core, directed by Dhruv Sareen, PhD, with support from the David and Janet Polak Foundation Stem Cell Core Laboratory, first converted adult human skin cells into powerful induced pluripotent stem cells (iPSC), which can be expanded indefinitely and then made into any cell of the human body. In this study, these induced pluripotent stem cells were then directed toward a neural progenitor cell fate, known as induced neural progenitor stem cells, or iNPCs.

"These induced neural progenitor stem cells are a novel source of adult-derived cells which should have powerful effects on slowing down vision loss associated with macular degeneration," said Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and contributing author to the study. "Though additional pre-clinical data is needed, our institute is close to a time when we can offer adult stem cells as a promising source for personalized therapies for this and other human diseases."

Next steps include testing the efficacy and safety of the stem cell injection in preclinical animal studies to provide information for applying for an investigational new drug. From there, clinical trials will be designed to test potential benefit in patients with later-stage age-related macular degeneration.

###

Additional Cedars-Sinai authors include Dhruv Sareen, PhD; Yuchun Tsai, PhD; Bin Lu, MD, PhD; Benjamin Bakondi, PhD; Sergey Girman, PhD; and Anais Sahabian, PhD.

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Stem cell injection may soon reverse vision loss due to age-related macular degeneration

Hockey great Gordie Howe makes gritty fight back from stroke

By Stem Cell Treatment

LUBBOCK, Texas (AP) Ravaged by a stroke that left him unable to walk and barely able to speak, Gordie Howe decided it was time to quit.

His sons didn't want to hear it. Not from Mr. Hockey, whose 25-year career in the NHL was defined by his indomitable style and blend of grit and finesse.

"He was saying, 'Take me out back and shoot me,'" recalled Murray Howe, a diagnostic radiologist. "He was serious. It wasn't like a joke. I said, 'Dad, let's just see if we can help you first.'"

They found it in Mexico, where experimental stem cell treatments produced what his family called a "life-changing" turnaround that has put the 87-year-old Howe back on his feet. A second round of treatments is planned in June.

These days there's little doubt his spirits are high. At a recent session of occupational and physical therapy in Lubbock, Howe's eyes twinkled and he smiled now and then as he flirted with the two young women putting him through his paces. He even planted an innocent, light kiss on the cheek on his occupational therapist and twirled her once as if dancing.

"He is doing extremely well, very well for his age," said Nathalie Geddie, Howe's physical therapist, adding that he still has weakness on his right side. "To think about how far he's come since he's had his stroke, he's made significant functional gains."

Recent years have indeed been challenging for Howe, who set NHL marks with 801 goals and 1,850 points mostly with the Detroit Red Wings that held up until Wayne Gretzky surpassed him. He retired from hockey for good, but not until he was 52.

The body he counted on as an athlete has stayed relatively strong, but memory loss from the early stages of dementia became a problem even before his wife's death in 2009 after battling Pick's disease, a rare form of dementia similar to Alzheimer's. Colleen Howe's death seemed to hasten Howe's decline, Murray Howe said.

Howe's four children began taking turns having him live at their homes for weeks or months at a time.

Howe had a significant stroke Oct. 26, losing use of his right arm and leg, and his speech was slurred. He was still able to recognize people in family photos and those from his playing days, and he improved in the weeks that followed. But because he couldn't swallow following the stroke, he shed 35 pounds. And then came another blow the next month.

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Hockey great Gordie Howe makes gritty fight back from stroke

Brainstorm Cell Therapeutics (BCLI) Stock Gains Today on Potentially Positive Phase 2a Results

By Stem Cell Treatment

NEW YORK (TheStreet) -- Brainstorm Cell Therapeutics (BCLI) shares are up 9.13% to $5.02 as the biopharmaceutical company's stock gains momentum after the company announced that it will present positive results fromits phase 2a study of NurOwn when it releases the full set of data next weekat the American Academy of Neurology annual meeting.

The Israel-based developer of adult stem cell technologies for neurodegenerative diseases is developing NurOwn, a treatment being tested on patients with ALS or Lou Gehrig's disease, which is designed as a cell therapyin which bone marrow-derived mesenchymal stem cells are induced to secretfactors known to promote neuronal survival.

"We are thrilled to have the opportunity to share our results at this prestigious venue, and we look forward to discussing these findings with the medical community," said CEOTony Fiorino, MD, PhD. BCLI data by YCharts

Must Read: Warren Buffett's Top 25 Stocks for 2015

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Brainstorm Cell Therapeutics (BCLI) Stock Gains Today on Potentially Positive Phase 2a Results

Dr. Raj, Top Beverly Hills Orthopedic Doctor, Appears on The Doctors TV Show Performing Successful Stem Cell Therapy

By Stem Cell Medicine

Beverly Hills, California (PRWEB) April 13, 2015

Dr. Raj, who is the top orthopedic surgeon in Los Angeles and Beverly Hills, appeared on The Doctors TV show this week performing successful stem cell therapy. The patient received an outpatient stem cell procedure for bilateral labral tears in the shoulders, with an incredible outcome displayed on the show.

The segment can be viewed here: http://www.thedoctorstv.com/videos/stem-cells-instead-of-surgery

For years, Dr. Raj has been helping patients avoid invasive surgeries with outpatient, low risk stem cell procedures. The focus of the segment on The Doctors was a patient who was having severe functional limitations due to her shoulder injuries. She could not drive without pain or do any regular activities such as brushing her hair or reaching overhead without immediate pain.

While being interviewed on the show four days after the procedure, Jennifer stated, "This is crazy. What's really shocking is I can put my arms above my head, I haven't done that in 10 years!"

Dr. Raj, as he has done for hundreds of patients, first aspirated some of the patients bone marrow. Then the marrow was processed immediately to concentrate the stem cells and growth factors. The processed marrow was then injected bilaterally into her shoulders along with numbing medicine, and then the procedure was done.

After four days the patient appeared with Dr. Raj on the show. She was able to painlessly drive, lift her arms above her head, and was truly amazed at the outcome in such a short time. Dr. Raj was asked if her result was typical.

He replied, "Stem cells are so magical. I've seen this frequently, it is expected."

Host Dr. Travis Stork then said, "I'm a fan if you can avoid a true surgery. It's all about the beauty of more options. This just adds another option in the arsenal."

For over 5 years, Dr. Raj has been named a Top Doctor in Southern California, Beverly Hills, Los Angeles and Nationally as well. He serves as an ABC News Medical Correspondent as well as a WebMD expert. National newspapers and television networks often turn to Dr. Raj for perspective on orthopedic injuries and treatments.

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Dr. Raj, Top Beverly Hills Orthopedic Doctor, Appears on The Doctors TV Show Performing Successful Stem Cell Therapy

Researchers identify drug target for ATRA, the first precision cancer therapy

By Stem Cell Medical Center

Targeted cancer therapies work by blocking a single oncogenic pathway to halt tumor growth. But because cancerous tumors have the unique ability to activate alternative pathways, they are often able to evade these therapies -- and regrow. Moreover, tumors contain a small portion of cancer stem cells that are believed to be responsible for tumor initiation, metastasis and drug resistance. Thus, eradicating cancer stem cells may be critical for achieving long-lasting remission, but there are no drugs available that specifically attack cancer stem cells.

Now a research team led by investigators in the Cancer Research Institute at Beth Israel Deaconess Medical Center (BIDMC), has identified an inhibitor of the Pin1 enzyme that can address both of these challenges in acute promyelocytic leukemia (APL) and triple negative breast cancer.

Their surprising discovery demonstrates that the vitamin A derivative ATRA (all-trans retinoic acid), a treatment for APL that is considered to be the first example of modern targeted cancer therapy, can block multiple cancer-driving pathways and, at the same time, eliminate cancer stem cells by degrading the Pin1 enzyme. Reported online in Nature Medicine, these novel findings suggest a promising new way to fight cancer -- particularly cancers that are aggressive or drug resistant.

"Pin1 changes protein shape through proline-directed phosphorylation, which is a major control mechanism for disease," explains co-senior author Kun Ping Lu, MD, PhD, Director of Translational Therapeutics in the Cancer Research Institute at BIDMC and Professor of Medicine at Harvard Medical School who co-discovered the enzyme in 1996. "Pin1 is a common key regulator in many types of cancer, and as a result, can control over 50 oncogenes and tumor suppressors, many of which are known to also control cancer stem cells."

Until now, agents that inhibit Pin1 have been developed mainly through rational drug design. Although these inhibitors have proven to be active against Pin1 in the test tube, when they are tested in vitro in a cell model or in vivo in a living animal they are unable to efficiently enter cells to successfully inhibit Pin1 function.

In this new work, co-senior author Xiao Zhen Zhou, MD, an investigator in BIDMC's Division of Translational Therapeutics and Assistant Professor at Harvard Medical School, decided to take a different approach to identify Pin1 inhibitors: She developed a mechanism-based high throughput screen to identify compounds that were targeting active Pin1.

"We had previously identified Pin1 substrate-mimicking peptide inhibitors," explains Zhou. "We therefore used these as a probe in a competition binding assay and screened approximately 8,200 chemical compounds, including both approved drugs and other known bioactive compounds." To increase screening success, Zhou chose a probe that specifically binds to the Pin1 enzyme active site very tightly, an approach that is not commonly used for this kind of screen.

"Initially, it appeared that the screening results had no positive hits, so we had to manually sift through them looking for the one that would bind to Pin1. We eventually spotted cis retinoic acid, which has the same chemical formula as all-trans retinoic acid [ATRA], but with a different chemical structure." It turned out, Zhou explains, that Pin1 prefers binding to ATRA and cis retinoic acid needs to convert ATRA in order to bind Pin1.

ATRA was first discovered for the treatment of acute promyelocytic leukemia (APL) in 1987. "Before tamoxifen or other targeted drugs, there was ATRA," says Lu. It was originally thought that ATRA was successfully treating APL by inducing cell differentiation, causing cancer cells to change into normal cells by activating the cellular retinoic acid receptors. But as these new findings reveal, although this differentiation activity is obvious, it is not the mechanism that is actually behind ATRA's successful outcomes in treating APL.

"While it has been previously shown that ATRA's ability to degrade the leukemia-causing fusion oncogene PML-RAR causes ATRA to stop the leukemia stem cells that drive APL, the underlying mechanism has remained elusive," says Lu. "Our new high throughput drug screening has revealed the ATRA drug target, unexpectedly showing that ATRA directly binds, inhibits and ultimately degrades active Pin1 selectively in cancer cells. The Pin1-ATRA complex structure suggests that ATRA is trapped in the Pin1 active site by mimicking an unreleasable enzyme substrate. Importantly, ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RAR and treats APL in cell and animal models as well as in human patients.

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Researchers identify drug target for ATRA, the first precision cancer therapy

One type of airway cell can regenerate another lung cell type

By Uncategorized

Findings from animal study have implications for disorders such as chronic obstructive pulmonary disease

IMAGE:Adult lung cells regenerating: Type 1 cells are green. Type 2 cells are red. New Type 2 derived from Type 1 cells are yellow. Nuclei are blue view more

Credit: Jon Epstein, MD & Rajan Jain, MD, Perelman School of Medicine at the University of Pennsylvania, and Christina Barkauskas & Brigid Hogan, Duke University

PHILADELPHIA - A new collaborative study describes a way that lung tissue can regenerate after injury. The team found that lung tissue has more dexterity in repairing tissue than once thought. Researchers from the Perelman School of Medicine at the University of Pennsylvania and Duke University, including co-senior authors Jon Epstein, MD, chair of the department of Cell and Developmental Biology, and Brigid L.M Hogan, Duke Medicine, along with co-first authors Rajan Jain, MD, a cardiologist and instructor in the Department of Medicine and Christina E. Barkauskas, also from Duke, report their findings in Nature Communications

"It's as if the lung cells can regenerate from one another as needed to repair missing tissue, suggesting that there is much more flexibility in the system than we have previously appreciated," says Epstein. "These aren't classic stem cells that we see regenerating the lung. They are mature lung cells that awaken in response to injury. We want to learn how the lung regenerates so that we can stimulate the process in situations where it is insufficient, such as in patients with COPD [chronic obstructive pulmonary disease]."

The two types of airway cells in the alveoli, the gas-exchanging part of the lung, have very different functions, but can morph into each other under the right circumstances, the investigators found. Long, thin Type 1 cells are where gases (oxygen and carbon dioxide) are exchanged - the actual breath. Type 2 cells secrete surfactant, a soapy substance that helps keep airways open. In fact, premature babies need to be treated with surfactant to help them breathe.

The team showed in mouse models that these two types of cells originate from a common precursor stem cell in the embryo. Next, the team used other mouse models in which part of the lung was removed and single cell culture to study the plasticity of cell types during lung regrowth. The team showed that Type 1 cells can give rise to Type 2 cells, and vice-versa.

The Duke team had previously established that Type 2 cells produce surfactant and function as progenitors in adult mice, demonstrating differentiation into gas-exchanging Type 1 cells. The ability of Type I cells to give rise to alternate lineages had not been previously reported.

"We decided to test that hypothesis about Type 1 cells," says Jain. "We found that Type 1 cells give rise to the Type 2 cells over about three weeks in various models of regeneration. We saw new cells growing back into these new areas of the lung. It's as if the lung knows it has to grow back and can call into action some Type 1 cells to help in that process."

This is one of the first studies to show that a specialized cell type that was thought to be at the end of its ability to differentiate can revert to an earlier state under the right conditions. In this case, it was not by using a special formula of transcription factors, but by inducing damage to tell the body to repair itself and that it needs new cells of a certain type to do that.

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One type of airway cell can regenerate another lung cell type

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