Stem Cell Clinic

Stem cells to repair broken chromosomes

By Stem Cell Doctors

(Ivanhoe Newswire) CLEVELAND, Ohio -- In 1990 the Human Genome Project started. It was a massive scientific undertaking that aimed to identify and map out the body's complete set of DNA. This research has paved the way for new genetic discoveries; one of those has allowed scientists to study how to fix bad chromosomes.

Our bodies contain 23 pairs of them, 46 total. But if chromosomes are damaged, they can cause birth defects, disabilities, growth problems, even death.

Case Western scientist Anthony Wynshaw-Boris is studying how to repair damaged chromosomes with the help of a recent discovery. He's taking skin cells and reprogramming them to work like embryonic stem cells, which can grow into different cell types.

You're taking adult or a child's skin cells. You're not causing any loss of an embryo, and you're taking those skin cells to make a stem cell. Anthony Wynshaw-Boris, M.D., PhD, of Case Western Reserve University, School of Medicine told Ivanhoe.

Scientists studied patients with a specific defective chromosome that was shaped like a ring. They took the patients' skin cells and reprogrammed them into embryonic-like cells in the lab. They found this process caused the damaged ring chromosomes to be replaced by normal chromosomes.

It at least raises the possibility that ring chromosomes will be lost in stem cells, said Dr. Wynshaw-Boris.

While this research was only conducted in lab cultures on the rare ring-shaped chromosomes, scientists hope it will work in patients with common abnormalities like Down syndrome.

What we're hoping happens is we might be able to use, modify, what we did, to rescue cell lines from any patient that has any severe chromosome defect, Dr. Wynshaw-Boris explained.

It's research that could one day repair faulty chromosomes and stop genetic diseases in their tracks.

The reprogramming technique that transforms skin cells to stem cells was so ground-breaking that a Japanese physician won the Nobel Prize in medicine in 2012 for developing it.

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Stem cells to repair broken chromosomes

New hope for Parkinsons patients in stem cell treatment

By Stem Cell Treatment

For more than 30 years, stem cells have been the great hope of medical science. Given their remarkable ability to turn into any type of cell in the body, researchers have theorized that they could be used to treat and perhaps even cure all sorts of diseases and conditions from spinal cord injury to baldness.

Progress has been painfully slow for most areas of research but this week researchers in Sweden are reporting a major advancein a possible stem cell treatment for Parkinson's. While the treatment has only been tried in rats, the scientists -- led byMalin Parmar, an associate professor of regenerative neurobiology at the Lund University -- said they believe the results are promising enoughto move to clinical trials in humans within a few years.

A degenerative condition of the central nervous system, Parkinson's affects an estimated 7 to 10 million people worldwide. Actor Michael J. Fox has Parkinson's and Google co-founder Sergey Brin has a gene that makes him susceptible to the disease. Both have not only raised awareness of the disease through their celebrity but have contributed millions of dollars to advance research.

Parkinson's is caused by the loss of dopamine-producing cells in the brain that help regulate things like movement and emotions. The scientistsat the Lund University found that when they turned human embryonic stem cells into neurons that produce dopamine and injected them into the brains of rats, something remarkable happened. The damage from the disease seemed to reverse.

The scientists wrote that while they believe their research was "rigorous," they pointed out that "a number of crucial issues" still need to be addressed before the treatment can be tested in humans. For instance, they need to make sure the cells continue to work the way they are supposed to over longer time periods.

Read more:

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Growing stem cells using cloning techniques reopens ethics debate

Dance for Parkinson's: movement as medicine

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New hope for Parkinsons patients in stem cell treatment

FDA Clears ISCO's Parthenogenetic Stem Cells For Investigational Clinical Use

By Stem Cell Treatment

By Cyndi Root

International Stem Cell Corporation is now approved to manufacture human parthenogenetic stem cells. The Food and Drug Administration (FDA) cleared the cells for investigational clinical use. The company announced the approval in a press release, stating that it improves its chance for approval of its Parkinsons disease treatment and provides an avenue for using the cells in other indications such as stroke or traumatic brain injury.

Dr. Ruslan Semechkin, ISCO's Chief Scientific Officer, said, "Many stem cell lines can never be used to develop commercial therapeutic products because they don't meet the FDA's ethical and quality standards. With this clearance from the FDA, the Company has removed any uncertainty in the potential clinical use of human parthenogenetic stem cells."

FDA Action

Like all manufacturing to FDA standards, stem cells must be produced in good manufacturing practice (GMP) conditions. The cells must be grown under repeatable conditions and be identical, so that patients receive standardized stem cell therapy. In addition, the federal agency seeks to reduce the risk of an infectious disease. ISCO provided the FDA assurances relating to the original egg donor's risk of infectious diseases, the testing of the master cell bank, and the genetic stability of the stem cell line. ISCO intends to produce the stem cells at its facility in Oceanside, CA and will provide an update on the first batch later.

Parthenogenetic Stem Cells

ISCO states that its parthenogenetic stem cells (hpSCs) are a new class of stem cells with the best characteristics of other stem cells. The company creates the cells by stimulating the donors oocytes (eggs), which are not fertilized and are not viable embryos. Stimulating the oocytes begins the process of cell division. This method creates cells that are histocompatiblethey do not depend on the target patient. Immunomatching and using unfertilized oocytes provides an ethical advantage and a reliable source for cell-based therapy.

Parkinson's Disease Submission

Dr. Semechkin stated the FDA manufacturing approval provides a boost to its Parkinson's disease submission, which the company intends to submit by the end of 2014. ISCO provided an update on the program in October 2014, stating that none of the preclinical pharmacology and toxicology studies have shown adverse events or pathological reactions. ISCO intends to present the results of those studies at the Society for Neuroscience annual meeting.

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FDA Clears ISCO's Parthenogenetic Stem Cells For Investigational Clinical Use

Human stem cell-derived neuron transplants reduce seizures in mice

By Stem Cell Treatment

McLean Hospital and Harvard Stem Cell Institute scientists have new evidence that stem cell transplantation could be a worthwhile strategy to help epileptics who do not respond to anti-seizure drugs.

As reported in Cell Stem Cell, the laboratory of McLean Associate Neurobiologist Sangmi Chung, PhD, transplanted seizure-inhibiting, human embryonic stem cell-derived neurons into the brains of mice with a common form of epilepsy. Half of the mice who received the transplanted neurons no longer had seizures, while the other half experienced a significant drop in seizure frequency.

"After the transplantation we observed that the human neurons integrate into the epileptic brain," said Chung, who is also a Harvard Stem Cell Institute affiliated faculty member and an assistant professor at Harvard Medical School. "The transplanted neurons begin to receive excitatory input from host neurons and in turn generate inhibitory responses that reverse the electrical hyperactivity that cause seizures."

The recovery seen after the human stem cell-derived neuron transplants, which were done while the cells were still maturing into their full-grown form, is similar to that published in a 2013 study by University of California, San Francisco, scientists who transplanted fetal mouse brain cells into epileptic mice.

While encouraging, Chung noted that further primate studies and a process to purify the neurons, so only those known to inhibit seizures are transplanted (called interneurons), would need to be completed before a treatment in humans could be considered.

"Because embryonic stem cells can differentiate into many different cell types, even when we drive them into neurons, there are always other cell types," she said. "For clinical purposes, we need to make sure the cells are safe, without any contaminant. Currently we are working on a different method to specifically isolate interneurons."

Over 65 million people worldwide are affected by epileptic seizures, which can cause convulsions, loss of consciousness and other neurological symptoms. The exact cause of the condition is unknown, but it is hypothesized that diminished populations of interneurons is a contributor.

Most epileptic patients can be treated with anti-seizure drugs, which contain molecules that can inhibit electrical symptoms, similar to the normal function of interneurons. But about one-third do not benefit from existing medication. Patients may opt to have a portion of their brain cut out to control symptoms.

"This seems to be an area that needs a novel therapy," Chung said. "Before starting this project, I was a stem cell biologist mostly interested in the development of neural stem cells, but as I've come to know about epilepsy, I've become motivated to continue this research."

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Human stem cell-derived neuron transplants reduce seizures in mice

Experimental treatments planned in teen's miraculous cancer fight

By Stem Cell Doctors

After four surgeries, nine kinds of chemotherapy, stem cell transplants, 14 radiation treatments and antibody treatments, Katie Hawley beat cancer. Twice.

Katie, then 9, learned she had cancer in 2009, when doctors found an egg-sized, stage 3 tumor in her stomach, the cause of her pain and nausea. The rare tumor strikes fewer than 5 of every 1 million children each year, according to the National Institute of Health.

In my heart, I hoped and believed she would beat this and live to 100, said Mary Kay Hawley, Katies mom. Yet, that quiet voice would whisper the nightmarish words, She may not make it to her 10th birthday. With that, I became her court jester I wanted to give her the world.

After she endured a yearlong battle with ganglio neuroblastoma, doctors found no evidence of cancer cells left in her body. For more than two years, the Ladera Ranch girl lived like a normal kid again aside from scans every three months.

Until the day before Valentines Day last year, when one of her routine CT scans showed the cancer had returned with a vengeance, spreading to her skull, hips and legs.

I was terrified that I was going to lose her, Hawley said. She fell to her knees and begged God to spare her daughter. I prayed until I had peace.

Katie, now a freshman at San Juan Hills High, was sent to undergo an experimental, strong chemotherapy treatment in San Francisco. She had a 33 percent chance of improvement, a 33 percent chance the disease would stay the same and 33 percent chance it would get worse. There was a 1 percent chance the treatment would kill the cancer cells, Hawley said.

Katie turned out to be the 1 percent and had a scan clear of cancer in June last year.

KEEPING THE CANCER AT BAY

To stop the cancer from returning, Katie was put on an aggressive, 10-month, in-home chemotherapy with Accutane treatments, making her extremely sick, tired and depressed, Hawley said. She took 14 pills a day, went to the hospital twice a week for blood tests and checkups and continued with CT scans every three months to check that the cancer hadnt returned.

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Experimental treatments planned in teen's miraculous cancer fight

Before there will be blood: Pro-inflammatory signaling plays surprising role in creation of hematopoietic stem cells

By Stem Cell Medicine

8 hours ago In this multiple confocal analysis of transverse sections from transgenic zebrafish embryos, vasculature is labeled by red fluorescence, NF-kB protein complex that regulates inflammation by green fluorescence and nuclei by blue fluorescence. The arrowhead indicates a potential hematopoietic stem cell emerging in the dorsal aorta with high expression of NF-kB. The image at bottom right combines all channels. Credit: UC San Diego School of Medicine

Hematopoietic stem cells (HSCs) give rise to all blood and immune cells throughout the life of vertebrate organisms, from zebrafish to humans. But details of their genesis remain elusive, hindering efforts to develop induced pluripotent stem cell (iPSC) replacements that might address a host of blood disorders.

In a paper published Nov. 20 in the journal Cell, researchers at the University of California, San Diego School of Medicine describe the surprising and crucial involvement of a pro-inflammatory signaling protein in the creation of HSCs during embryonic development, a finding that could help scientists to finally reproduce HSCs for therapeutic use.

"The recent breakthrough of induced pluripotency has made the concept of patient-specific regenerative medicine a reality," said principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine. "The development of some mature cell lineages from iPSCs, such as cardiac and neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all of the factors used by the embryo to generate HSCs. We believe the discovery that pro-inflammatory cues are important in vivo will help us recapitulate instruction of HSC fate in vitro from iPSCs."

Traver and colleagues specifically looked at the role of a cytokine (a type of cell signaling protein) called tumor necrosis factor alpha or TNF, which plays a pivotal role in regulating systemic inflammation and immunity. The work extended previous research by Spanish biologist Victoriano Mulero, who had reported that TNF was important in the function of the embryonic vascular system and that in animal models where TNF function was absent, blood defects resulted.

The Cell paper's first author Raquel Espin-Palazon, a postdoctoral researcher in Traver's lab and a former colleague of Mulero's, determined that TNF was required for the emergence of hematopoietic stem cells during embryogenesis in zebrafish a common animal model.

Traver said the finding was completely unexpected because HSCs emerge relatively early in embryonic formation when the developing organism is considered to be largely sterile and devoid of infection.

"Thus, there was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions," Traver said. "Equally surprising, we found that a population of embryonic myeloid cells, which are transient cells produced before HSCs arise, are the producers of the TNF needed to establish HSC fate. So it turns out that a small subset of myeloid cells that persist for only a few days in development are necessary to help generate the lineal precursors of the entire adult blood-forming system."

The newly discovered role of TNF in HSC development mirrors a parallel discovery regarding interferon gamma (INFg), another cytokine and major mediator of pro-inflammatory signaling, highlighting multiple inputs for inflammatory signaling in HSC emergence. Traver said the crucial roles of TNF and INFg in HSC emergence are likely similar in humans because of the highly conserved nature of HSC development across vertebrate evolution.

Explore further: New blood: Tracing the beginnings of hematopoietic stem cells

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Before there will be blood: Pro-inflammatory signaling plays surprising role in creation of hematopoietic stem cells

Before There Will Be Blood

By Stem Cell Medicine

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Newswise Hematopoietic stem cells (HSCs) give rise to all blood and immune cells throughout the life of vertebrate organisms, from zebrafish to humans. But details of their genesis remain elusive, hindering efforts to develop induced pluripotent stem cell (iPSC) replacements that might address a host of blood disorders.

In a paper published Nov. 20 in the journal Cell, researchers at the University of California, San Diego School of Medicine describe the surprising and crucial involvement of a pro-inflammatory signaling protein in the creation of HSCs during embryonic development, a finding that could help scientists to finally reproduce HSCs for therapeutic use.

The recent breakthrough of induced pluripotency has made the concept of patient-specific regenerative medicine a reality, said principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine. The development of some mature cell lineages from iPSCs, such as cardiac and neural, has been reasonably straightforward, but not with HSCs. This is likely due, at least in part, to not fully understanding all of the factors used by the embryo to generate HSCs. We believe the discovery that pro-inflammatory cues are important in vivo will help us recapitulate instruction of HSC fate in vitro from iPSCs.

Traver and colleagues specifically looked at the role of a cytokine (a type of cell signaling protein) called tumor necrosis factor alpha or TNFa, which plays a pivotal role in regulating systemic inflammation and immunity. The work extended previous research by Spanish biologist Victoriano Mulero, who had reported that TNFa was important in the function of the embryonic vascular system and that in animal models where TNF function was absent, blood defects resulted.

The Cell papers first author Raquel Espin-Palazon, a postdoctoral researcher in Travers lab and a former colleague of Muleros, determined that TNFa was required for the emergence of hematopoietic stem cells during embryogenesis in zebrafish a common animal model.

Traver said the finding was completely unexpected because HSCs emerge relatively early in embryonic formation when the developing organism is considered to be largely sterile and devoid of infection.

Thus, there was no expectation that pro-inflammatory signaling would be active at this time or in the blood-forming regions, Traver said. Equally surprising, we found that a population of embryonic myeloid cells, which are transient cells produced before HSCs arise, are the producers of the TNFa needed to establish HSC fate. So it turns out that a small subset of myeloid cells that persist for only a few days in development are necessary to help generate the lineal precursors of the entire adult blood-forming system.

The newly discovered role of TNFa in HSC development mirrors a parallel discovery regarding interferon gamma (INFg), another cytokine and major mediator of pro-inflammatory signaling, highlighting multiple inputs for inflammatory signaling in HSC emergence. Traver said the crucial roles of TNFa and INFg in HSC emergence are likely similar in humans because of the highly conserved nature of HSC development across vertebrate evolution.

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Before There Will Be Blood

Scientists find that SCNT derived cells and IPS cells are similar

By Stem Cell Medical Center

8 hours ago

A team led by New York Stem Cell Foundation (NYSCF) Research Institute scientists conducted a study comparing induced pluripotent stem (iPS) cells and embryonic stem cells created using somatic cell nuclear transfer (SCNT). The scientists found that the cells derived from these two methods resulted in cells with highly similar gene expression and DNA methylation patterns. Both methods also resulted in stem cells with similar amounts of DNA mutations, showing that the process of turning an adult cell into a stem cell introduces mutations independent of the specific method used. This suggests that both methods of producing stem cells need to be further investigated before determining their suitability for the development of new therapies for chronic diseases.

The NYSCF Research Institute is one of the only laboratories in the world that currently pursues all forms of stem cell research including SCNT and iPS cell techniques for creating stem cells. The lack of laboratories attempting SCNT research was one of the reasons that the NYSCF Research Institute was established in 2006.

"We do not yet know which technique will allow scientists to create the best cells for new cellular therapies," said Susan L. Solomon, NYSCF CEO and co-founder. "It is critical to pursue both SCNT and iPS cell techniques in order to accelerate research and bring new treatments to patients."

While both techniques result in pluripotent stem cells, or cells that can become any type of cell in the body, the two processes are different. SCNT consists of replacing the nucleus of a human egg cell or oocyte with the nucleus of an adult cell, resulting in human embryonic stem cells with the genetic material of the adult cell. In contrast, scientists create iPS cells by expressing a few key genes in adult cells, like a skin or blood cell, causing the cells to revert to an embryonic-like state. These differences in methods could, in principle, result in cells with different properties. Advances made earlier this year by NYSCF Research Institute scientists that showed that human embryonic stem cells could be derived using SCNT revived that debate.

"Our work shows that we now have two methods for the generation of a patient's personal stem cells, both with great potential for the development of treatments of chronic diseases. Our work will also be welcome news for the many scientists performing basic research on iPS cells. It shows that they are likely working with cells that are very similar to human embryonic stem cells, at least with regard to gene expression and DNA methylation. How the finding of mutations might affect clinical use of stem cells generated from adult cells is the subject of an ongoing debate," said Dr. Dieter Egli, NYSCF Senior Research Fellow, NYSCF - Robertson Investigator, Assistant Professor in Pediatrics & Molecular Genetics at Columbia University, and senior author on the paper.

The study, published today in Cell Stem Cell, compared cell lines derived from the same sources using the two differing techniques, specifically contrasting the frequency of genetic coding mutations seen and measuring how closely the stem cells matched the embryonic state through the analysis of DNA methylation and of gene expression patterns. The scientists showed that both methods resulted in cell types that were similar with regard to gene expression and DNA methylation patterns. This suggested that both methods were effective in turning a differentiated cell into a stem cell.

The scientists also showed that cells derived using both SCNT and iPS techniques showed similar numbers of genetic coding mutations, implying that neither technique is superior in that regard. A similar number of changes in DNA methylation at imprinted genes (genes that are methylated differentially at the maternal versus the paternal allele) were also found. It is important to note that both types of techniques led to cells that had more of these aberrations than embryonic stem cells derived from an unfertilized human oocyte, or than embryonic stem cells derived from leftover IVF embryos. These findings suggest that a small number of defects are inherent to the generation of stem cells from adult differentiated cells and occur regardless of the method used.

Explore further: Some stem cell methods closer to 'gold standard' than others

Researchers around the world have turned to stem cells, which have the potential to develop into any cell type in the body, for potential regenerative and disease therapeutics. Now, for the first time, researchers ...

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Scientists find that SCNT derived cells and IPS cells are similar

Scientists create Parkinson's disease in a dish

By Stem Cell Medical Center

PUBLIC RELEASE DATE:

6-Nov-2014

Contact: David McKeon dmckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation @nyscf

New York, NY (November 6, 2014) - A team of scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute successfully created a human stem cell disease model of Parkinson's disease in a dish. Studying a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson's disease, another unrelated Parkinson's patient, and four healthy control subjects, the scientists were able to observe key features of the disease in the laboratory, specifically differences in the patients' neurons' ability to produce dopamine, the molecule that is deficient in Parkinson's disease. In addition, the scientists also identified a potential strategy for developing novel therapies for Parkinson's disease.

Attributed to a combination of genetic and nongenetic factors, Parkinson's disease has no completely effective therapy or cure. Parkinson's disease is moderately heritable, but the mechanisms of this inheritance are not well understood. While genetic forms of the disease exist, sporadic forms are far more common.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," said Susan L. Solomon, NYSCF Chief Executive Officer. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson's disease; however, only 30% of individuals with this mutation have been shown to develop Parkinson's disease by the age of 80. This discordance suggests that multiple factors contribute to the development of Parkinson's disease, including both genetic and non-genetic factors. To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.

In this study, published today in Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson's disease in one twin, and the lack of disease in the other. The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson's in a dish, recapitulating key features of the disease, specifically the accumulation of -synuclein and dopamine deficiency.

Upon analyzing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated -synuclein protein levels, and a reduced capacity to synthesize and release dopamine. In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other. Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalized -synuclein and dopamine levels in the cell models. This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.

"The subject of Parkinson's disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease," said Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF - Charles Evans Senior Research Fellow for Alzheimer's Disease. "Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson's disease patients and other neurodegenerative disorders."

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Scientists create Parkinson's disease in a dish

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