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Twin copies of gene pair up in embryonic stem cells at critical moment in differentiation

By Stem Cell Medicine

Both copies of the Oct4 gene physically come together just as embryonic stem cells begin to develop into tissue-specific cell types

IMAGE:We and other mammals have two copies of each gene, and each copy, or 'allele,' was thought to remain physically apart from the other in the cell nucleus. David Spector's... view more

Credit: Spector Lab, CSHL

Cold Spring Harbor, NY -- Imagine a pair of twins that everyone believed to be estranged, who turn out to be closer than anyone knew. A genetic version of this heartwarming tale might be taking place in our cells. We and other mammals have two copies of each gene, one from each parent. Each copy, or "allele," was thought to remain physically apart from the other in the cell nucleus, but a new study finds that alleles can and do pair up in mammalian cells.

Intriguingly, the pairing of at least one set of alleles has been observed to coincide with a critical time in the life of a stem cell: the moment when it commits to develop into a specific cell type. This process is called differentiation.

In work published today in Cell Stem Cell a team of researchers led by Professor David L. Spector at Cold Spring Harbor Laboratory (CSHL) showed that the two alleles of Oct4, a gene important in embryonic stem cells, did not come together randomly, at any time or place, but did so at the developmental point at which stem cells begin their maturation into specific cell types.

Spector, along with Megan Hogan, Ph.D., lead author on the new paper, and colleagues, began by observing the location within the cell nucleus of various genes known to be important in stem cells. "We examined hundreds of cells, and we made the interesting and unexpected finding that the two alleles of the Oct4 gene tended to co-localize together in about 25% of the cells," Spector says. "This was really unexpected, but it's the sort of image that's worth a thousand words."

Examining enough single cells to make sure the team was observing a widespread phenomenon was no easy task. "It was a lot of work, but I think in the end the pictures that come out of it, the stories that we have gotten out if it, makes it worth it," says Hogan, a recent doctoral student in the Spector Lab and now a postdoctoral investigator at the Icahn School of Medicine at Mount Sinai.

To figure out if what they were seeing was physiologically important, the team studied whether they could manipulate the timing of the Oct4 pairing during differentiation. They used different methods to cause the stem cells to differentiate, and found that the more rapidly the cells differentiated, the earlier Oct4 pairing occurred. "This supported the notion that this was a potentially very exciting finding," Spector says.

To confirm that the Oct4 pairing wasn't something that only occurred in tissue culture, the team then looked in mouse embryos. "The pairing was equal to or even a little bit more frequent than in culture, and that was really comforting and extremely convincing to us that there is physiological relevance to this," Spector says.

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Twin copies of gene pair up in embryonic stem cells at critical moment in differentiation

New ALS gene and signaling pathways identified

By Stem Cell Medical Center

IMAGE:Induced pluripotent stem cell-derived motor neurons from an ALS patient (left) compared with normal cells (right). The cells are being used to study the role of the genes TBK1 and... view more

NEW YORK, NY (February 19, 2015)--Using advanced DNA sequencing methods, researchers have identified a new gene that is associated with sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. ALS is a devastating neurodegenerative disorder that results in the loss of all voluntary movement and is fatal in the majority of cases. The next-generation genetic sequencing of the exomes (protein-coding portions) of 2,874 ALS patients and 6,405 controls represents the largest number of ALS patients to have been sequenced in a single study to date.

Though much is known about the genetic underpinnings of familial ALS, only a handful of genes have been definitively linked to sporadic ALS, which accounts for about 90 percent of all ALS cases. The newly associated gene, called TBK1, plays a key role at the intersection of two essential cellular pathways: inflammation (a reaction to injury or infection) and autophagy (a cellular process involved in the removal of damaged cellular components). The study, conducted by an international ALS consortium that includes scientists and clinicians from Columbia University Medical Center (CUMC), Biogen Idec, and HudsonAlpha Institute for Biotechnology, was published today in the online edition of Science.

"The identification of TBK1 is exciting for understanding ALS pathogenesis, especially since the inflammatory and autophagy pathways have been previously implicated in the disease," said Lucie Bruijn, PhD, Chief Scientist for The ALS Association. "The fact that TBK1 accounts for one percent of ALS adds significantly to our growing understanding of the genetic underpinnings of the disease. This study, which combines the efforts of over two dozen laboratories in six countries, also highlights the global and collaborative nature of ALS research today.

"This study shows us that large-scale genetic studies not only can work very well in ALS, but that they can help pinpoint key biological pathways relevant to ALS that then become the focus of targeted drug development efforts," said study co-leader David B. Goldstein, PhD, professor of genetics and development and director of the new Institute for Genomic Medicine at CUMC. "ALS is an incredibly diverse disease, caused by dozens of different genetic mutations, which we're only beginning to discover. The more of these mutations we identify, the better we can decipher--and influence--the pathways that lead to disease." The other co-leaders of the study are Richard M. Myers, PhD, president and scientific director of HudsonAlpha, and Tim Harris, PhD, DSc, Senior Vice President, Technology and Translational Sciences, Biogen Idec.

"These findings demonstrate the power of exome sequencing in the search for rare variants that predispose individuals to disease and in identifying potential points of intervention. We are following up by looking at the function of this pathway so that one day this research may benefit the patients living with ALS," said Dr. Harris. "The speed with which we were able to identify this pathway and begin our next phase of research shows the potential of novel, focused collaborations with the best academic scientists to advance our understanding of the molecular pathology of disease. This synergy is vital for both industry and the academic community, especially in the context of precision medicine and whole-genome sequencing."

"Industry and academia often do things together, but this is a perfect example of a large, complex project that required many parts, with equal contributions from Biogen Idec. Dr. Tim Harris, our collaborator there, and his team, as well as David Goldstein and his team, now at Columbia University, as well as our teams here at HudsonAlpha, said Dr. Myers. "I love this research model because it doesn't happen very frequently, and it really shows how industry, nonprofits, and academic laboratories can all work together for the betterment of humankind. The combination of those groups with a large number of the clinical collaborators who have been seeing patients with this disease for many years and providing clinical information, recruiting patients, as well as collecting DNA samples for us to do this study, were all critical to get this done."

Searching through the enormous database generated in the ALS study, Dr. Goldstein and his colleagues found several genes that appear to contribute to ALS, most notably TBK1 (TANK-Binding Kinase 1), which had not been detected in previous, smaller-scale studies. TBK1 mutations appeared in about 1 percent of the ALS patients--a large proportion in the context of a complex disease with multiple genetic components, according to Dr. Goldstein. The study also found that a gene called OPTN, previously thought to play a minor role in ALS, may actually be a major player in the disease.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," said Dr. Goldstein. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

The researchers are currently using patient-derived induced pluripotent embryonic stem cells (iPS cells) and mouse models with mutations in TBK1 or OPTN to study ALS disease mechanisms and to screen for drug candidates. Several compounds that affect TBK1 signaling have already been developed for use in cancer, where the gene is thought to play a role in tumor-cell survival.

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New ALS gene and signaling pathways identified

The International Society for Stem Cell Research announces annual meeting details

By Stem Cell Clinic

CHICAGO -- The International Society for Stem Cell Research's 13th annual meeting will take place June 24-27, 2015 at the Stockholmsmssan Exhibition and Convention Center in Stockholm, Sweden. The meeting will bring together approximately 4,000 stem cell scientists, bioethicists, clinicians and industry professionals from over 50 countries to present and discuss the latest discoveries and technologies within the field.

"The ISSCR is excited to bring its annual meeting to Stockholm, a city that shares our passion and reputation for great scientific research and collaboration," said ISSCR President Rudolf Jaenisch, M.D., Whitehead Institute for Biomedical Research. "We look forward to learning more about the strong work being done in Sweden and across Europe."

The meeting will open with the Presidential Symposium on June 24 from 1:15-3:15 p.m. local time. The symposium sets the stage for the meeting with world renowned speakers, including Nobel Prize winner Shinya Yamanaka. It is also the platform for the formal recognition of the 2015 recipients of the McEwen Award for Innovation and the ISSCR Public Service Award. Another prestigious award, the ISSCR-BD Biosciences Outstanding Young Investigator Award, will be presented during Plenary VI on June 27 from 9-11:20 a.m. and followed by an award lecture.

"I look forward to the Presidential Symposium setting the tone for the entire program," Jaenisch said. "A thread throughout will be the use of stem cells to drive our understanding of development and disease, as we explore disease modeling, gene and tissue engineering technologies and other important advances that are bringing stem cells into the clinic."

Presidential Symposium speakers will include:

Fred H. Gage, Ph.D., Salk Institute for Biological Sciences, U.S.

Jrgen Knoblich, Ph.D., Institute of Molecular Biotechnology, Austria

Shinya Yamanaka, M.D., Ph.D., Center for iPS Cell Research & Application, Japan

Jeannie Lee, M.D., Ph.D., Massachusetts General Hospital, U.S.

The McEwen Award for Innovation award winners (Presidential Symposium):

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The International Society for Stem Cell Research announces annual meeting details

New reporter system to study bone-related regenerative medicine generated by UMN labs

By Stem Cell Clinic

MINNEAPOLIS/ST. PAUL (2/10/2015) - A new reporter system used to study the bone regeneration potential of human embryonic stem cells has been generated in research led by the University of Minnesota. The new reporter system is the first of its kind for human pluripotent stem cells and is important for identifying certain agents and pathways that mediate early stages of human bone development.

The research is published today in the journal Stem Cell Reports.

The RUNX2-yellow fluorescent protein reporter system allows researchers to learn whether a human pluripotent stem cell-derived cell tests positive (or negative) for certain properties. Cells testing positive have been shown previously to repair bone in the skulls of immunodeficient mice. An improved understanding of whether a cell tests positive or negative through the RUNX2-yellow fluorescent protein reporter system will allow researchers to better monitor which types of cells produced from human pluripotent stem cells might be best suited to regenerating bone.

The Stem Cell Reports publication comes on the heels of a complementary finding led by the same group of University of Minnesota researchers published in December in the journal Stem Cells. The Stem Cells publication specified a new reporter system to identify and isolate a unique group of progenitor blood cells from human pluripotent stem cells. The ability to isolate this unique group of cells will likely impact the scientific community's potential to generate human blood cells from human pluripotent stem cells, with the potential to produce new therapies for patients to better treat diseases such as leukemia or genetic blood disorders.

The bone-related reporter system will now be used to test potential new therapeutic compounds at the University's Institute for Therapeutics Discovery & Development. Mayo Clinic and the University of Minnesota School of Dentistry contributed to the finding supported by National Institutes of Health and National Institute of Dental and Craniofacial Research grants DE022556 and R90 DE023058.

"While we've developed these reporters in other systems including animals in the past, we haven't previously done this in human-specific cells," said Dan Kaufman, M.D., Ph.D., corresponding author of the publication, professor of medicine at the University of Minnesota Medical School, and Stem Cell Institute and Masonic Cancer Center member. "Human cells allow us to better translate new therapies from the lab to humans, and learn more about how early bone and blood cells are made."

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The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school's 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Visit med.umn.edu to learn more.

Masonic Cancer Center, University of Minnesota is part of the University's Academic Health Center. It is designated by the National Cancer Institute as a Comprehensive Cancer Center. For more information about the Masonic Cancer Center, visit cancer.umn.edu or call 612-624-2620.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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New reporter system to study bone-related regenerative medicine generated by UMN labs

British biotech firm sets crowdfunding record with heart drug

By Uncategorized

Published February 10, 2015

A British biotech company founded by a Nobel prize winner has raised what it says is a record 691,000 pounds ($1 million) via crowdfunding to help launch a stem cell-based regenerative medicine for use following heart trauma.

Cell Therapy, based in the Welsh capital Cardiff, says the medicine has the potential to reduce scarring of the heart muscle caused by a heart attack or failure.

Chief Executive Ajan Reginald, previously at Roche, said crowd funding was a quick way to raise money for final stage trials or commercial launches.

"It was very fast and very efficient," he told Reuters on Monday. "We have spent 5 percent of our time on fundraising, which enables me to spend 95 percent of my time on the business."

The company, whose founder Martin Evans shared the 2007 Nobel Prize for medicine for groundbreaking stem cell research, used website Crowdcube to raise nearly three times its original target from more than 300 investors.

Reginald said the backers included investment bankers, hedge fund employees and scientists.

"Crowd funding allows investors to look in detail at a company in their own time," he said, adding that some 10,000 investors had seen the pitch.

The company would publish data from clinical trials of the drug, called Heartcel, next month, before final stage trials with a view to a launch in 2016.

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British biotech firm sets crowdfunding record with heart drug

A good night's sleep keeps your stem cells young

By Uncategorized

Under normal conditions, many of the different types of tissue-specific adult stem cells, including hematopoietic stem cells, exist in a state or dormancy where they rarely divide and have very low energy demands. "Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging," says Dr. Michael Milsom, leader of the study.

However, under conditions of stress, such as during chronic blood loss or infection, hematopoietic stem cells are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue. "It's like forcing you out of your bed in the middle of the night and then putting you into a sports car and asking you to drive as fast as you can around a race circuit while you are still half asleep," explains Milsom. "The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA and coordinate cell division. Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong."

Indeed, experiments described in the study show that the increased energy demands of the stem cells during stress result in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time that the cell is trying to replicate its DNA, then this can cause either the death of the stem cell, or potentially the acquisition of mutations that may cause cancer.

Normal stem cells can repair the majority of this stress-induced DNA damage, but the more times you are exposed to stress, the more likely it is that a given stem cell will inefficiently repair the damage and then die or become mutated and act as a seed in the development of leukemia. "We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older," Milsom adds.

In addition, the study goes on to examine how this stress response impacts on a mouse model of a rare inherited premature aging disorder that is caused by a defect in DNA repair. Patients with Fanconi anemia suffer a collapse of their blood system and have an extremely high risk of developing cancer. Mouse models of Fanconi anemia have exactly the same DNA repair defect as found in human patients but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.

"We felt that stress induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice," says Milsom. When Fanconi anemia mice were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage and their stem cells failed. In the same space of time that normal mice showed a gradual decline in hematopoietic stem cell numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.

"This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it," commented Milsom.

Prof. Dr. Andreas Trumpp, director of HI-STEM and head of the Division of Stem Cells and Cancer at the DKFZ believes that this work is a big step towards understanding a range of age-related diseases. "The novel link between physiologic stress, mutations in stem cells and aging is very exciting," says Trumpp, a co-author of the study. "By understanding the mechanism via which stem cells age, we can start to think about strategies to prevent or at least reduce the risk of damaged stem cells which are the cause of aging and the seed of cancer."

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Dagmar Walter, Amelie Lier, Anja Geiselhart, Frederic B. Thalheimer, Sina Huntscha, Mirko C. Sobotta, Bettina Moehrle, David Brocks, Irem Bayindir, Paul Kaschutnig, Katja Muedder, Corinna Klein, Anna Jauch, Timm Schroeder, Hartmut Geiger, Tobias P. Dick, Tim Holland-Letz, Peter Schmezer, Steven W. Lane, Michael A. Rieger, Marieke A. G. Essers, David A. Williams, Andreas Trumpp und Michael D. Milsom: Exit from dormancy provokes DNA damage-induced attrition in haematopoietic stem cells. Nature 2015, DOI: 10.1038/nature14131

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A good night's sleep keeps your stem cells young

Okyanos Stem Cell Therapy Launches Orthopedic Lifestyle Survey

By Uncategorized

Freeport, Grand Bahama (PRWEB) March 09, 2015

Okyanos, the leader in cell therapy, launched its next in a series of studies today to determine the emotional impact and lifestyle influence orthopedic conditions such as osteoarthritis and sports-related injuries have had on those affected. The survey focuses on people between the ages of 55 and 75 living with orthopedic health issues and is designed to examine the toll on those afflicted as well as their relationships.

According to Okyanos VP Marketing Carol Montgomery, Millions of people suffer disorders of the joints, bones, muscles and connective ligaments, tendons and cartilage debilitating conditions on a daily basis, ranging from reduced function to crippling pain but have exhausted available methods of treatment. These restrictions affect them in a variety of ways and our ongoing lifestyle surveys measure the effects such chronic conditions have on todays aging population. Many are turning to solutions like adult stem cell therapy for treatment with excellent results.

The Okyanos Lifestyle and Relationship Survey for Heart Disease, of nearly 700 adults, uncovered a staggering 93% were open to alternatives to their existing heart disease treatment plan showing a growing discontent with their current options. A majority 68% were emotionally impacted and felt they were saddled with restrictions imposed by their heart conditions such as chronic fatigue and shortness of breath.

Adult stem cell therapy has emerged as a new treatment alternative for those who are restricted in activities they can no longer do but are determined to live a more normal life. Okyanos cell therapy uses a unique blend of adult stem and regenerative cells derived from a patients own fat tissue, thereby utilizing the bodys own natural biology to heal itself.

Just 50 miles from US shore, Okyanos cell therapy is available to patients suffering with the daily discomfort of orthopedic conditions including osteoarthritis, rheumatoid arthritis, sports-related injuries and spine disease.

Patients with a severe orthopedic condition, interested in participating in the study can go to: https://www.surveymonkey.com/s/ortho_Okyanos

For a copy of the Okyanos Heart Disease Lifestyle Report that reveals the emotional toll and lifestyle impact heart disease has on patients in the United States, visit: Heart Disease Lifestyle Report

Patients can contact Okyanos to learn more and request a free consultation at http://www.Okyanos.com or by calling 1-855-659-2667.

About Okyanos: (Oh key AH nos) Based in Freeport, Grand Bahama, Okyanos brings a new standard of care and a better quality of life to patients with coronary artery disease, tissue ischemia, autoimmune diseases, and other chronic neurological and orthopedic conditions. Okyanos Cell Therapy utilizes a unique blend of stem and regenerative cells derived from patients own adipose (fat) tissue which helps improve blood flow, moderate destructive immune response and prevent further cell death. Okyanos is fully licensed under the Bahamas Stem Cell Therapy and Research Act and adheres to U.S. surgical center standards. The literary name Okyanos, the Greek god of the river Okyanos, symbolizes restoration of blood flow.

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Okyanos Stem Cell Therapy Launches Orthopedic Lifestyle Survey

MS stem cell treatment hailed 'miraculous' as patients make dramatic recovery

By Stem Cell Treatment

Pioneering treatment has allowed wheelchair-bound patients to run again Patient given high dose of chemotherapy to wipe out faulty immune system Therapy then uses person's own stem cells to fight the devastating disease It may be the first ever treatment tosuccessfullyreverse symptoms of MS

By Fiona Macrae for the Daily Mail

Published: 13:27 EST, 1 March 2015 | Updated: 02:54 EST, 2 March 2015

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Britons left wheelchair-bound by multiple sclerosis can walk, run and even dance again after being given a pioneering stem cell treatment.

Doctors have described the recoveries as miraculous, while patients say they have been given their lives back.

The treatment uses a patients own stem cells the bodys master cells to fight the disease.

Recovery: MS sufferer Holly Drewerybecame wheelchair-bound after the birth of daughter Isla, but thanks tothe stem cell transplant shecan dance, run and chase after Isla in the park

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MS stem cell treatment hailed 'miraculous' as patients make dramatic recovery

'Miraculous' stem-cell treatment reverses symptoms of multiple sclerosis

By Stem Cell Treatment

A new stem-cell treatment that reboots the entire immune system is enabling multiple sclerosis sufferers to walk, run and even dance again, in results branded "miraculous" by doctors.

Patients who have been wheelchair-bound for 10 years have regained the use of their legs in the ground-breaking therapy, while others who were blind can now see again. The treatment is the first to reverse the symptoms of MS, which is incurable, and affects about 100,000 people in Britain.

The two dozen patients who are taking part in the trials at the Royal Hallamshire Hospital, Sheffield, and Kings College Hospital, London, have effectively had their immune systems "rebooted". Although it is unclear what causes MS, some doctors believe it is the immune system itself that attacks the brain and spinal cord, leading to inflammation pain, disability and, in severe cases, death.

In the new treatment, specialists use a high dose of chemotherapy to knock out the immune system before rebuilding it with stem cells taken from the patient's own blood.

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"Since we started treating patients three years ago, some of the results we have seen have been miraculous," Prof Basil Sharrack, a consultant neurologist at Sheffield Teaching Hospitals NHS Foundation Trust, said.

"This is not a word I would use lightly, but we have seen profound neurological improvements."

Holly Drewry, 25, of Sheffield, was wheelchair bound after the birth of her daughter, Isla, two years ago. She claims the new treatment has transformed her life.

"It worked wonders," she said. "I remember being in the hospital ... after three weeks, I called my mum and said: 'I can stand'. We were all crying. I can run a little bit, I can dance. I love dancing, it is silly but I do."

However, specialists warn that patients need to be fit to benefit from the new treatment.

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'Miraculous' stem-cell treatment reverses symptoms of multiple sclerosis

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