Stem Cell Clinic

Stem cells faulty in Duchenne muscular dystrophy, Stanford researchers find

By Stem Cell Clinic

PUBLIC RELEASE DATE:

17-Dec-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

Like human patients, mice with a form of Duchenne muscular dystrophy undergo progressive muscle degeneration and accumulate connective tissue as they age. Now, researchers at the Stanford University School of Medicine have found that the fault may lie at least partly in the stem cells that surround the muscle fibers.

They've found that during the course of the disease, the stem cells become less able to make new muscle and instead begin to express genes involved in the formation of connective tissue. Excess connective tissue -- a condition called fibrosis -- can accumulate in many organs, including the lungs, liver and heart, in many different disorders. In the skeletal muscles of people with muscular dystrophy, the fibrotic tissue impairs the function of the muscle fibers and leads to increasing weakness and stiffness, which are hallmarks of the disease.

The researchers discovered that this abnormal change in stem cells could be inhibited in laboratory mice by giving the animals a drug that is already approved for use in humans. The drug works by blocking a signaling pathway involved in the development of fibrosis. Although much more research is needed, the scientists are hopeful that a similar approach may one day work in children with muscular dystrophy.

"These cells are losing their ability to produce muscle, and are beginning to look more like fibroblasts, which secrete connective tissue," said Thomas Rando, MD, PhD, professor of neurology and neurological sciences. "It's possible that if we could prevent this transition in the muscle stem cells, we could slow or ameliorate the fibrosis seen in muscular dystrophy in humans."

A paper describing the researchers' findings will be published Dec. 17 in Science Translational Medicine. Rando, the paper's senior author, is director of the Glenn Laboratories for the Biology of Aging and founding director of the Muscular Dystrophy Association Clinic at Stanford. Former postdoctoral scholar Stefano Biressi, PhD, is the lead author. Biressi is now at the Centre for Integrative Biology at the University of Trento in Italy.

A devastating disease

Duchenne muscular dystrophy is a devastating disease that affects about 1 in every 3,600 boys born in the United States. Patients usually experience severe, progressive muscle weakness that confines them to a wheelchair in early adolescence and eventually leads to paralysis. It's caused by mutations in the dystrophin gene, which encodes the dystrophin protein. The dystrophin protein serves to connect muscle fibers to the surrounding external matrix. This connection stabilizes the fibers, enhancing their strength and preventing injury. Sufferers are nearly always boys because the dystrophin gene is located on the X chromosome. (Girls would need to inherit two faulty copies, which is unlikely because male carriers often die in early adulthood.)

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Stem cells faulty in Duchenne muscular dystrophy, Stanford researchers find

Press Conference for Researcher Accused of Fraud Becomes TV Phenomenon in Japan

By Stem Cell Doctors

TOKYO Live broadcasts of scientist Haruko Obokata's press conference, in which she defended her groundbreaking stem cell research against allegations of data fabrication, were a ratings hit on multiple TV networks and online platforms on Wednesday.

The event in a hotel in Osaka attracted 300 members of the domestic and international media, and was broadcast live on most of Japan's major networks. Nihon Terebi (NTV) topped the ratings with 12.3 percent, with public broadcaster NHK in second with 9.4 percent and Tokyo Broadcasting Systems (TBS) in third with 6.8 percent, according to Video Research Inc.

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The press conference was scheduled to run for 30 minutes, but ended up lasting more than two hours, as Obokata, age 30, sometimes struggled to answer questions from hostile members of the media. TV networks extended news programs and shifted schedules to continue coverage.

TV Tokyo, famous for ignoring major news events and sticking with its regular schedule, went ahead with an episode of Law & Order, followed by straight-to-video Canadian action movie Recoil.

The Wednesday lunchtime event attracted more than 1.26 million to a live Ustream broadcast and 550,000 viewers to a live stream on Nico Nico Douga, a Japanese online video platform that allows users to post comments on-screen in real time. More than 690,000 comments were posted during the course of the press conference.

Around 112,500 Tweets relating to the events at the press conference were sent in two hours.

STORY: Japan's Fuji TV Links With Crunchyroll to Stream Dramas in the U.S.

Obokata, who had been hailed as a pioneer in Japan's male-dominated scientific world, was hospitalized on Monday suffering from stress, and faced the media against the advice of doctors.

In January, Obokata was hailed as a scientific star in the local media after what appeared to be groundbreaking stem cell research by a team she led was published in British scientific journal Nature. Stories about the researcher, who spent two years at Harvard, focused on her cute apron worn in place of a traditional lab coat, and how she had persevered in the face of adversity.

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Press Conference for Researcher Accused of Fraud Becomes TV Phenomenon in Japan

Four clinics face action over stem-cell treatment claims

By Stem Cell Treatment

The wife of well-known former monk Mitsuo Shibahashi, previously known as Phra Mitsuo Gavesako, owns one of the clinics. The department began looking into their operation after one patient complained about losing more than Bt2 million on the treatment. The patient was treated for and hopes to recover from a brain infarction (stroke or blood clot).

Probes reveal the clinics allegedly provided basic check-ups before arranging for their customers to get stem-cell injections in Germany. "According to the Medical Council's regulations, stem-cell treatment is allowed for blood-related diseases only," the department's director-general Boonruang Triruangwor-awat said yesterday.

He said three of the four clinics had clearly violated rules about advertising medical services. "[Their] benefits are exaggerated," he said,

The four clinics are located in CentralWorld, Ekkamai area, Soi Thonglor 55, and Ploenchit Centre.

Boonruang said these clinics could be punished under Article 34(2) of the Medical Facilities Act.

"Offenders face a jail term of up to one year or a maximum fine of Bt20,000," he said.

He added that his department was also in the process of seeking the Medical Council's ruling to determine if these clinics could be punished under Article 49.

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Four clinics face action over stem-cell treatment claims

University of Toronto cell biologists discover on-off switch for key stem cell gene – Discovery may propel advances in …

By Stem Cell Medicine

TORONTO, ON Consider the relationship between an air traffic controller and a pilot. The pilot gets the passengers to their destination, but the air traffic controller decides when the plane can take off and when it must wait. The same relationship plays out at the cellular level in animals, including humans. A region of an animals genome the controller directs when a particular gene the pilot can perform its prescribed function.

A new study by cell and systems biologists at the University of Toronto (U of T) investigating stem cells in mice shows, for the first time, an instance of such a relationship between the Sox2 gene which is critical for early development, and a region elsewhere on the genome that effectively regulates its activity. The discovery could mean a significant advance in the emerging field of human regenerative medicine, as the Sox2 gene is essential for maintaining embryonic stem cells that can develop into any cell type of a mature animal.

We studied how the Sox2 gene is turned on in mice, and found the region of the genome that is needed to turn the gene on in embryonic stem cells, said Professor Jennifer Mitchell of U of Ts Department of Cell and Systems Biology, lead investigator of a study published in the December 15 issue of Genes & Development.

Like the gene itself, this region of the genome enables these stem cells to maintain their ability to become any type of cell, a property known as pluripotency. We named the region of the genome that we discovered the Sox2 control region, or SCR, said Mitchell.

Since the sequencing of the human genome was completed in 2003, researchers have been trying to figure out which parts of the genome made some people more likely to develop certain diseases. They have found that the answers are more often in the regions of the human genome that turn genes on and off.

If we want to understand how genes are turned on and off, we need to know where the sequences that perform this function are located in the genome, said Mitchell. The parts of the human genome linked to complex diseases such as heart disease, cancer and neurological disorders can often be far away from the genes they regulate, so it can be difficult to figure out which gene is being affected and ultimately causing the disease.

It was previously thought that regions much closer to the Sox2 gene were the ones that turned it on in embryonic stem cells. Mitchell and her colleagues eliminated this possibility when they deleted these nearby regions in the genome of mice and found there was no impact on the genes ability to be turned on in embryonic stem cells.

We then focused on the region weve since named the SCR as my work had shown that it can contact the Sox2 gene from its location 100,000 base pairs away, said study lead author Harry Zhou, a former graduate student in Mitchells lab, now a student at U of Ts Faculty of Medicine. To contact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embryonic stem cells. Once we had a good idea that this region could be acting on the Sox2 gene, we removed the region from the genome and monitored the effect on Sox2.

The researchers discovered that this region is required to both turn Sox2 on, and for the embryonic stem cells to maintain their characteristic appearance and ability to differentiate into all the cell types of the adult organism.

Just as deletion of the Sox2 gene causes the very early embryo to die, it is likely that an abnormality in the regulatory region would also cause early embryonic death before any of the organs have even formed, said Mitchell. It is possible that the formation of the loop needed to make contact with the Sox2 gene is an important final step in the process by which researchers practicing regenerative medicine can generate pluripotent cells from adult cells.

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University of Toronto cell biologists discover on-off switch for key stem cell gene - Discovery may propel advances in ...

Cutting Out the Cellular Middleman: New Technology Directly Reprograms Skin Fibroblasts For a New Role

By Uncategorized

PHILADELPHIA As the main component of connective tissue in the body, fibroblasts are the most common type of cell. Taking advantage of that ready availability, scientists from the Perelman School of Medicine at the University of Pennsylvania, the Wistar Institute, Boston University School of Medicine, and New Jersey Institute of Technology have discovered a way to repurpose fibroblasts into functional melanocytes, the body's pigment-producing cells. The technique has immediate and important implications for developing new cell-based treatments for skin diseases such as vitiligo, as well as new screening strategies for melanoma. The work was published this week in Nature Communications.

The new technique cuts out a cellular middleman. Study senior author Xiaowei George Xu, MD, PhD, an associate professor of Pathology and Laboratory Medicine, explains, "Through direct reprogramming, we do not have to go through the pluripotent stem cell stage, but directly convert fibroblasts to melanocytes. So these cells do not have tumorigenicity."

Changing a cell from one type to another is hardly unusual. Nature does it all the time, most notably as cells divide and differentiate themselves into various types as an organism grows from an embryo into a fully-functional being. With stem cell therapies, medicine is learning how to tap into such cell specialization for new clinical treatments. But controlling and directing the process is challenging. It is difficult to identify the specific transcription factors needed to create a desired cell type. Also, the necessary process of first changing a cell into an induced pluripotent stem cell (iPSC) capable of differentiation, and then into the desired type, can inadvertently create tumors.

Xu and his colleagues began by conducting an extensive literature search to identify 10 specific cell transcription factors important for melanocyte development. They then performed a transcription factor screening assay and found three transcription factors out of those 10 that are required for melanocytes: SOX10, MITF, and PAX3, a combination dubbed SMP3.

"We did a huge amount of work," says Xu. "We eliminated all the combinations of the other transcription factors and found that these three are essential."

The researchers first tested the SMP3 combination in mouse embryonic fibroblasts, which then quickly displayed melanocytic markers. Their next step used a human-derived SMP3 combination in human fetal dermal cells, and again melanocytes (human-induced melanocytes, or hiMels) rapidly appeared. Further testing confirmed that these hiMels indeed functioned as normal melanocytes, not only in cell culture but also in whole animals, using a hair-patch assay, in which the hiMels generated melanin pigment. The hiMels proved to be functionally identical in every respect to normal melanocytes.

Xu and his colleagues anticipate using their new technique in the treatment of a wide variety of skin diseases, particularly those such as vitiligo for which cell-based therapies are the best and most efficient approach.

The method could also provide a new way to study melanoma. By generating melanocytes from the fibroblasts of melanoma patients, Xu explains, "we can screen not only to find why these patients easily develop melanoma, but possibly use their cells to screen for small compounds that can prevent melanoma from happening."

Perhaps most significantly, say the researchers, is the far greater number of fibroblasts available in the body for reprogramming compared to tissue-specific adult stem cells, which makes this new technique well-suited for other cell-based treatments.

The research was supported by the National Institutes of Health (R01-AR054593, P30-AR057217)

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Cutting Out the Cellular Middleman: New Technology Directly Reprograms Skin Fibroblasts For a New Role

New technology directly reprograms skin fibroblasts for a new role

By Uncategorized

As the main component of connective tissue in the body, fibroblasts are the most common type of cell. Taking advantage of that ready availability, scientists from the Perelman School of Medicine at the University of Pennsylvania, the Wistar Institute, Boston University School of Medicine, and New Jersey Institute of Technology have discovered a way to repurpose fibroblasts into functional melanocytes, the body's pigment-producing cells. The technique has immediate and important implications for developing new cell-based treatments for skin diseases such as vitiligo, as well as new screening strategies for melanoma. The work was published this week in Nature Communications.

The new technique cuts out a cellular middleman. Study senior author Xiaowei "George" Xu, MD, PhD, an associate professor of Pathology and Laboratory Medicine, explains, "Through direct reprogramming, we do not have to go through the pluripotent stem cell stage, but directly convert fibroblasts to melanocytes. So these cells do not have tumorigenicity."

Changing a cell from one type to another is hardly unusual. Nature does it all the time, most notably as cells divide and differentiate themselves into various types as an organism grows from an embryo into a fully-functional being. With stem cell therapies, medicine is learning how to tap into such cell specialization for new clinical treatments. But controlling and directing the process is challenging. It is difficult to identify the specific transcription factors needed to create a desired cell type. Also, the necessary process of first changing a cell into an induced pluripotent stem cell (iPSC) capable of differentiation, and then into the desired type, can inadvertently create tumors.

Xu and his colleagues began by conducting an extensive literature search to identify 10 specific cell transcription factors important for melanocyte development. They then performed a transcription factor screening assay and found three transcription factors out of those 10 that are required for melanocytes: SOX10, MITF, and PAX3, a combination dubbed SMP3.

"We did a huge amount of work," says Xu. "We eliminated all the combinations of the other transcription factors and found that these three are essential."

The researchers first tested the SMP3 combination in mouse embryonic fibroblasts, which then quickly displayed melanocytic markers. Their next step used a human-derived SMP3 combination in human fetal dermal cells, and again melanocytes (human-induced melanocytes, or hiMels) rapidly appeared. Further testing confirmed that these hiMels indeed functioned as normal melanocytes, not only in cell culture but also in whole animals, using a hair-patch assay, in which the hiMels generated melanin pigment. The hiMels proved to be functionally identical in every respect to normal melanocytes.

Xu and his colleagues anticipate using their new technique in the treatment of a wide variety of skin diseases, particularly those such as vitiligo for which cell-based therapies are the best and most efficient approach.

The method could also provide a new way to study melanoma. By generating melanocytes from the fibroblasts of melanoma patients, Xu explains, "we can screen not only to find why these patients easily develop melanoma, but possibly use their cells to screen for small compounds that can prevent melanoma from happening."

Perhaps most significantly, say the researchers, is the far greater number of fibroblasts available in the body for reprogramming compared to tissue-specific adult stem cells, which makes this new technique well-suited for other cell-based treatments.

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New technology directly reprograms skin fibroblasts for a new role

New Procedure Gives Tulsan A Chance To Walk Using His Own Stem Cells

By Stem Cell Treatment

TULSA, Oklahoma -

It's a procedure that saved a Tulsa man from having knee surgery and his doctor says it's a revolution in medical care.

Doctors used Michael Conte's own stem cells to heal his damaged knee in a treatment that's only recently become available in Oklahoma.

To Michael Conte, breathing underwater is as much a part of his life as breathing fresh air. After all, he and his wife, both scuba instructors at Oral Roberts University were married under the sea in the Bahamas in 1992.

He works several jobs, is in the National Guard, mountain bikes, weight trains and walks. Michael is as active as a 49-year-old man as you'll find anywhere.

"I work at American, I'm in the military, I teach at ORU, I'm always on the go," said Michael Conte.

After a recent knee injury, you can imagine the disappointment when his doctor told Michael, he would have to slow down because he needed a knee replacement. So Michael started looking for other options.

"I'm definitely too I mean young to have a knee replacement. And they're only good for like ten years. So it doesn't really solve anything," said Michael Conte.

What he found was stem cell treatment and Dr. Venkatesh Movva in Tulsa. In a procedure, that until recently was only available in Europe, Regenexx uses a person's own stem cells to regenerate bad tissue in places like knees, hips, shoulders, ankles and elbows.

"We take your own stem cells, the patient's own stem cells from a reservoir of stem cells. Because we all have stem cells in different reservoirs," said Dr. Venkatesh Movva.

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New Procedure Gives Tulsan A Chance To Walk Using His Own Stem Cells

Jazz Pharma Begins Rolling NDA For Defibrotide In Hepatic VOD

By Stem Cell Treatment

By Estel Grace Masangkay

Jazz Pharmaceuticals announced that it has started the rolling submission of a New Drug Application (NDA) for defibrotide as treatment for severe hepatic veno-occlusive disease (VOD) in patients undergoing hematopoietic stem-cell transplantation (HSCT) therapy.

Defibrotide is approved and indicated in the EU as treatment for severe hepatic VOD in patients one month old and above undergoing HSCT therapy. The drug has also received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of VOD. The company announced earlier this year that it will acquire rights to defibrotide from Sigma-Tau Pharmaceuticals through Jazzs subsidiary Gentium.

Veno-occlusive disease is an early complication in patients under HSCT therapy. The therapy is performed to treat hematological malignancies, certain tumors, and other non-malignant disorders. Severe VOD can be deadly and is linked with multi-organ failure. The condition is fatal in 80 percent of patients.

Jazz presented analysis of positive results from a Phase 3 trial of defibrotide in severe hepatic VOD at the recent American Society of Hematology (ASH) 56th Annual Meeting and Exposition held in San Francisco, California.

Jeffrey Tobias, EVP and CMO of Jazz Pharmaceuticals, said, We expect to complete the submission of the NDA in the first half of 2015, at which time we will be requesting a Priority Review of the application, and we will continue to work closely with the FDA as we seek approval of the NDA. We will continue to provide patients access to defibrotide through an expanded access treatment protocol that is open under an ongoing investigational new drug application in the U.S.

The FDAs Fast Track designation enables faster development and review of drugs that treat serious, deadly conditions and that address significant unmet medical needs. The Fast Track rolling submission process permits a company to submit parts of its New Drug Application (NDA) for review as soon as they are completed instead of waiting until all sections of the application are available before submitting them as a whole.

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Jazz Pharma Begins Rolling NDA For Defibrotide In Hepatic VOD

Baby cells learn to communicate using the lsd1 gene

By Stem Cell Medical Center

21 hours ago Fruit fly ovarian follicle progenitor cells, with different colors marking a specific kind of activity (red) specific gene expression (green) and nuclear DNA (blue). Credit: Ming-Chia Lee and Allan Spradling

We would not expect a baby to join a team or participate in social situations that require sophisticated communication. Yet, most developmental biologists have assumed that young cells, only recently born from stem cells and known as "progenitors," are already competent at inter-communication with other cells.

New research from Carnegie's Allan Spradling and postdoctoral fellow Ming-Chia Lee shows that infant cells have to go through a developmental process that involves specific genes before they can take part in the group interactions that underlie normal cellular development and keep our tissues functioning smoothly. The existence of a childhood state where cells cannot communicate fully has potentially important implications for our understanding of how gene activity on chromosomes changes both during normal development and in cancerous cells. The work is published in Genes and Development.

The way that the molecules that package a cell's chromosomes are organized in order to control gene activity is known as the cell's "epigenetic state." The epigenetic state is fundamental to understanding Spradling and Lee's findings. To developmental biologists, changes in this epigenetic state ultimately explain how the cell's properties are altered during tissue maturation.

"In short, acquired epigenetic changes in a developing cell are reminiscent of the learned changes the brain undergoes during childhood," Spradling explained. "Just as it remains difficult to map exactly what happens in a child's brain as it learns, it is still very difficult to accurately measure epigenetic changes during cellular development. Not enough cells can usually be obtained that are at precisely the same stage for scientists to map specific molecules at specific chromosomal locations."

Lee and Spradling took advantage of the unsurpassed genetic tools available in the fruit fly to overcome these obstacles and provide new insight into the epigenetics of cellular development.

Using a variety of tools and techniques, they focused on cells in the fruit fly ovary and were able identify a specific gene called lsd1 that is needed for ovarian follicle progenitor cells to mature at their normal rate. The researchers found that the amount of the protein that is encoded by this gene, Lsd1, which is present in follicle progenitors decreases as the cells approach differentiation. What's more, the onset of differentiation could be shifted by changing the levels of Lsd1 protein that are present. They deduced that differentiation ensues when Lsd1 levels fall below a critical threshold, and that this likely corresponds to when genes can be stably expressed.

"The timing of differentiation is very important for normal development," Lee said. "Differentiation onset determines how many times progenitors divide, and even small perturbations in Lsd1 levels changed the number of follicle cells that were ultimately produced, which reduced ovarian function."

Previously, it was thought that the follicle cell progenitors started to differentiate based on an external signal they received from another kind of ovarian cells known as germ cells. Lee and Spradling found that while this germ cell signal was essential, it was already being regularly sent even before the progenitors responded. Instead, it was the Lsd1-mediated change in their epigenetic state that timed when progenitor cells started to respond to the signal and begun differentiating. Once they become competent, however, differentiating follicle cells communicate extensively with their neighbors, and continued to do so throughout their lives.

As is frequently the case in basic biological research, the molecules and mechanisms studied here are found in most multicellular animals and hence the researchers conclusions are likely to apply broadly throughout the animal kingdom, including in humans.

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Baby cells learn to communicate using the lsd1 gene

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