Stem Cell Clinic

New tool aids stem cell engineering for medical research

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PUBLIC RELEASE DATE:

28-Aug-2014

Contact: Robert Nellis newsbureau@mayo.edu 507-284-5005 Mayo Clinic

ROCHESTER, Minn. A Mayo Clinic researcher and his collaborators have developed an online analytic tool that will speed up and enhance the process of re-engineering cells for biomedical investigation. CellNet is a free-use Internet platform that uses network biology methods to aid stem cell engineering. Details of CellNet and its application to stem cell engineering are described in two back-to-back papers in the journal Cell.

"This free platform has a broad range of uses for all types of cell-based investigations and can potentially offer help to people working on all types of cancer," says Hu Li, Ph.D., investigator in the Mayo Clinic Center for Individualized Medicine and Department of Molecular Pharmacology & Experimental Therapeutics, and co-lead investigator in the two works. "CellNet will indicate how closely an engineered cell resembles the real counterpart and even suggests ways to adjust the engineering."

The network biology platform contains data on a wide range of cells and details on what is known about those cell types. Researchers say the platform can be applied to almost any study and allows users to refine the engineering process. In the long term, it should provide a reliable short cut to the early phases of drug development, individualized cancer therapies, and pharmacogenetics.

CellNet uses 21 cell types and tissues and data from 56 published human and mouse engineering studies as a basis for analyzing and predicting cell fate and corresponding engineering strategies. The platform also offers classification scores to determine differentiation and conversion of induced pluripotent stem cells. It reveals incomplete conversion of engineered microphages and hepatocytes. CellNet can be used for interrogation of cell fate following expression profiling, by classifying input by cell type, quantifying gene regulatory network status, and identifying aberrant regulators affecting the engineering process. All this is valuable in predicting success of engraftment of cancer tumors in mouse avatars for cancer and drug development research. CellNet can be accessed at cellnet.hms.harvard.edu.

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Co-lead authors with Dr. Li are Patrick Cahan, Ph.D., and Samantha Morris, Ph.D., of Boston Children's Hospital. The senior investigators are George Q. Daley, M.D., Ph.D., Director of the Stem Cell Transplantation Program at Boston Children's and senior investigator on both studies and James Collins, Ph.D., Core Faculty member at the Wyss Institute and the William F. Warren Distinguished Professor at Boston University, co-senior investigator on one of the studies.

Investigators are supported in part by the National Institutes of Health, specifically, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute; the Children's Hospital Stem Cell Program; the Howard Hughes Medical Institute; Alex's Lemonade Stand Foundation; the Ellison Medical Foundation; the Doris Duke Medical Foundation; the Mayo Clinic Center for Individualized Medicine and the Mayo Clinic Center for Regenerative Medicine.

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New tool aids stem cell engineering for medical research

Japan's Riken Reboots After Stem-Cell Scandal

By Stem Cell Medicine

By Dow Jones Business News, August 27, 2014, 12:55:00 AM EDT

TOKYO--A scandal that started with a few suspicious images has led Japan's most prestigious research institute to slash its stem-cell unit by half and acknowledge deeper flaws in its ethics.

The move by the Riken institute came seven months after the publication of papers that it initially hailed as equal in importance to the Copernican revolution in astronomy. Since then, the papers have been retracted, and one of the co- authors committed suicide.

On Wednesday, Riken said it would scale down to half its size the Center for Developmental Biology, rename the center and choose a new director with input from non-Japanese scientists, an indication of how the scandal has damaged the reputation of Japanese science.

"We believe it is important to move forward with the restructuring to improve the quality and promote honest research," said Ryoji Noyori, the Nobel Prize winner who leads Riken.

Riken's overhaul could also sway the field of stem-cell science, which has received billions of dollars in research funds in the hopes of cures for ailments such as diabetes and heart disease.

Some details of the overhaul, including whether anyone beside the director would indeed lose their job, remained murky. Nevertheless, science writer Shinya Midori said, "This could trigger scaling down in the field of regenerative medicine."

The scandal at Riken has deeply shaken the country's science establishment and the wider stem-cell world and sparked a debate about research ethics in Japan amid "results-first" pressure.

The drama has focused on the institute's 14-year-old developmental-biology center and erupted after one of its scientists, Haruko Obokata, was found guilty of manipulating data in a pair of papers published in the journal Nature. The studies, which claimed to show a groundbreaking method of making stem cells by dipping cells in a mild acid solution, were quickly challenged and Nature retracted the papers in July, saying they contained inaccurate data.

Riken initially stood by the 31-year-old Dr. Obokata, who had been hailed as a national hero after her research was first published, but later distanced itself from what it called her "sloppy data management" and poor research ethics.

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Japan's Riken Reboots After Stem-Cell Scandal

Pfizer buys into Cambridge life science innovation

By Stem Cell Medicine

Stem cell technology pioneer,DefiniGEN Ltdhas joined the Pfizer-inspired European Bank for induced pluripotent stem cells (EBiSC) consortium.

The consortium comprises 26 partners, and has been newly-formed with support from the Innovative Medicines Initiative (IMI) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

DefiniGen, a Cambridge University spin-out that has raised millions, represents one of the first commercial opportunities to arise from the universitys expertise in stem cells and is based on the research of Dr Ludovic Vallier, Dr Tamir Rashid and Professor Roger Pedersen of the universitys Anne McLaren Laboratory of Regenerative Medicine.

The EBiSC iPS cell bank will act as a central storage and distribution facility for human iPS cells, to be used by researchers across academia and industry in the study of disease and the development of new therapeutics. DefiniGENs role will be to validate EBiSC iPS cell lines by generating liver hepatocyte cells for toxicology, disease modelling, and regenerative medicine applications.

Dr Marcus Yeo, CEO of DefiniGEN, said: We are delighted to be a part of this ground-breaking consortium which will provide a crucial platform resource to enable the realisation of the full potential of iPS technology.

Conceptualised and coordinated by Pfizer Ltd in Cambridge, UK and managed by Roslin Cells Ltd in Edinburgh, the EBiSC bank aims to become the European go to resource for high quality research grade human iPS cells.

Today, iPS cells are being created in an increasing number of research programmes underway in Europe, but are not being systematically catalogued and distributed at the necessary scale to keep pace with their generation, nor to meet future demand.

The 35 million project will support the initial build of a robust, reliable supply chain from the generation of customised cell lines, the specification to internationally accepted quality criteria and their distribution to any global qualified user, ensuring accessibility to consistent, high quality tools for new medicines development.

Ruth McKernan, CSO of Pfizers Neusentis research unit in Cambridge, said: We are excited to be a part of this precompetitive collaboration to build a sustainable repository of high quality human iPS cell lines.

For many areas of research in academia and in industry, understanding the biological basis of disease heterogeneity is the next horizon. A bank of well-characterised iPS lines with strong relevance to the entire research community will help us all in our mission to bring therapies to patients.

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Pfizer buys into Cambridge life science innovation

Can stem cells help mobility after stroke?

By Stem Cell Medicine

MIAMI - When Bruce Daily woke up after having lumbar surgery a year ago, he realized he couldn't move the right side of his body.

"It took me a long while to figure out I wasn't gonna walk again," he said. "I knew I was down."

Daily, 69, had gone in for lumbar surgery at the University of Miami hospital and had an ischemic stroke while under anesthesia. An ischemic stroke results from an obstruction in a blood vessel that blocks the blood from getting to the brain.

Because he was unconscious, he missed the four-to-five hour-window to apply the tissue plasminogen activator, or tPA, the only medication available to treat ischemic strokes. The medication dissolves the clot, restoring blood flow to the brain.

But while he missed that chance, he was right on time to meet Dr. Dileep Yavagal, a neurosurgeon who practices at the University of Miami and Jackson Memorial hospitals. Yavagal was enrolling patients in RECOVER-stroke, a clinical trial treating recent stroke patients with stem cells from their bone marrow and applying them directly into the carotid artery, one of two arteries that supply the neck and head with blood. Daily was one of 47 patients nationwide who qualified for the study.

The study is funded by Cytomedix, the company that developed the technology to extract stem cells from bone marrow. The firm chose Yavagal to lead a national blind study at the end of 2012.

Yavagal enrolled 13 patients at the University of Miami/Jackson Memorial Hospital, between the end of 2012 and January of 2014. So far, the initial three-month results have revealed that the marrow cells are not doing any damage, and there was no clear difference between those who received the cells and those who didn't. The study's one-year final results will be revealed in January.

"There is severe need for developing treatment for ischemic stroke, and stem cells are the most promising," said Yavagal, whose own research is still in its initial phase, focusing on using a healthy donor's bone marrow stem cells versus the patient's own marrow.

Stroke, the leading cause of adult disability in the United States, and the No. 4 cause of death in the country, causes 130,000 deaths a year in the U.S., according to the Centers for Disease Control and Prevention.

Yavagal, associate professor of clinical neurology and neurosurgery and the director of interventional neurology at the University of Miami's Miller School of Medicine, said that restricted mobility or loss of speech resulting from a moderate to severe stroke can be devastating because patients often become dependent on someone else for daily activities.

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Can stem cells help mobility after stroke?

Iowa City-area research institute benefiting from ice bucket challenge

By Stem Cell Medical Center

By Erin Jordan, The Gazette

IOWA CITY An Iowa City-area research institute has received donations from around the world as Catholic organizations encourage members to route their Ice Bucket Challenge gifts to an organization that doesnt do research on embryonic stem cells.

The John Paul II Medical Research Institute, founded in 2008 by Dr. Alan Moy, an Iowa City pulmonologist, has gotten hundreds of thousands of dollars in donations from people who want to support research on Amyotrophic Lateral Sclerosis (ALS), but dont want the research done with human embryos, said CEO Jay Kamath.

We serve as an alternative to them to donate money that aligns with their values, Kamath said Wednesday.

The non-profit institute, which employs three researchers at the University of Iowas BioVentures Center in Coralville, has developed a platform for research on adult stem cells, but so far hasnt done any studies on ALS, he said.

We havent had the funding streams, Kamath said.

But thats changing.

Donations have been pouring in since Catholic organizations, such as the Archdiocese of Cincinnati and Archdiocese of St. Louis, issued statements encouraging Catholics to donate money to the institute rather than the ALS Association, which started the Ice Bucket Challenge July 29.

The challenge asks people to post videos of themselves being doused with icy water and/or make a donation to an ALS charity. The ALS Association has so far raised more than $94 million from the drive.

The Archdiocese of Dubuque is the latest group to ask Catholics to steer donations to the John Paul II institute.

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Iowa City-area research institute benefiting from ice bucket challenge

New Research Method Opens Door to Therapy with Human Muscle Stem Cells Promising Method Developed

By Stem Cell Clinic

27.08.2014 - (idw) Max-Delbrck-Centrum fr Molekulare Medizin (MDC) Berlin-Buch

Stem cells are essential for the repair of muscle damage, but all attempts to manipulate human muscle stem cells for therapy have thus far failed. Now Dr. Andreas Marg and Prof. Simone Spuler of the Experimental and Clinical Research Center (ECRC), a joint cooperation between the Max Delbrck Center (MDC) and the Charit, have shown how this might work. They developed a method in which they did not isolate the muscle stem cells, but rather cultivated, proliferated and transplanted them along with their muscle fibers. Using this method in mice, they were able to successfully regenerate muscle tissue. Thus they have opened the door for the use of muscle stem cells to treat muscle diseases.* "Muscle stem cells, which we also refer to as satellite cells, can awaken in their stem cell niche after decades of quiescence and can then repair damaged muscle tissue," Professor Spuler explained. At the ECRC in Berlin-Buch, the neurologist heads the University Outpatient Clinic for Muscle Disorders and the Department of Muscle Sciences. She and her team are exploring the causes of muscle diseases. Evidence shows that satellite cells are active in people with severe muscle diseases such as Duchenne muscular dystrophy, a severe genetic disease in which the muscles degenerate. "But at some point, she added, the reservoir is depleted of muscle stem cells and muscle wasting cannot be stopped."

All attempts to rebuild muscle tissue by transplanting satellite cells in patients with Duchenne muscular dystrophy have failed. The transplanted cells are not viable. Furthermore, the use of other cells with potential to regenerate muscle cells has shown little success. These cells have only limited potential to regenerate muscle. But how is it possible to nevertheless use the bodys own self-renewal potential and the reconstruction potential of satellite cells?

The offer of developmental biologist Professor Carmen Birchmeier (MDC) to participate in the network project on satellite cells (SatNet) of the Federal Ministry of Education and Research pointed Professor Spuler and her co-workers in the right direction. One of the topics of the project was to elucidate why satellite cells rapidly lose their regeneration potential if they are kept in a cell culture. This led to the idea to cultivate the satellite cells together with the surrounding muscle tissue to see whether the cells, if they remain in their accustomed milieu, might possibly regenerate better.

Muscle biopsy specimens from young and old donors After due approval and written, informed consent, Professor Spuler and Dr. Marg obtained specimens of fresh thigh muscle tissue from patients between 20 and 80 years of age from neurosurgeons of Helios Klinikum Berlin-Buch, which like the MDC is located close to the ECRC.

From the biopsy specimens, Professor Spuler and her co-workers dissected more than 1000 muscle fiber fragments, each about 2-3 millimeters long. Remarkably, the researchers found the number of stem cells in the individual tissue specimens to be independent of the age of the donor and that thousands of myoblasts developed from a small number of satellite cells. After further developmental steps, these fuse into muscle fibers.

Dr. Marg: Satellite cells need to have their local milieu around them Professor Spuler and her co-workers cultivated the muscle fiber fragments with the satellite cells, initially for up to three weeks. During this time, the satellite cells increased by 20- to 50-fold, but numerous connective tissue cells also developed in these cultures. To prevent this, the researchers concurrently subjected the muscle fragments to oxygen deprivation (hypoxia) and to cooling (hypothermia) at 4 degrees Celsius. Under these conditions, only satellite cells are able to survive in their stem cell niche, in contrast to the connective tissue cells. Apparently, the satellite cells receive the proper nutrients in their own local milieu, Dr. Marg said.

First success in mice The ECRC researchers then tried out their therapy approach in mice in which muscle regeneration had been inhibited by irradiation. They grafted the muscle fragments containing the satellite cells, which following the hypothermia had been kept for two weeks in culture dishes, into the tibalis anterior muscle. The researchers found that the muscles of animals that had been treated with these fiber fragments regenerated particularly well.

Objective: to couple satellite cells with gene therapy However, a genetic muscle disease cannot be successfully treated alone by transplanting muscle fragments. Professor Spuler: The idea is therefore to equip the satellite cells additionally with a healthy gene that repairs the defective gene and then to transfect it with the aid of a non-viral gene taxi into the muscles to be treated. In a first experiment with a reporter gene in the Petri dish, Professor Spuler and her co-workers proved that this is possible in principle. The reporter gene fluoresces green when it is transfected into the satellite cell. As gene taxi the researchers use the Sleeping Beauty transposon a jumping gene that can change its position in the genome. This transposon technique was developed several years ago by Dr. Zsuzsanna Izsvk (MDC) and Dr. Zoltn Ivics (Paul Ehrlich Institute, Frankfurt) and is considered to be a very promising delivery vehicle (vector) for gene therapy.

Before the method developed by Professor Spuler and her group can be used to benefit patients, some hurdles remain to be taken. So far, the transplantation has succeeded in small mice muscles. In clinical trials, the scientists and physicians want to determine whether this technique can be used in large human thigh muscles, which may be severely altered due to a muscular disease.

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New Research Method Opens Door to Therapy with Human Muscle Stem Cells Promising Method Developed

2 Cases Suggest Stem Cell Transplant Might Ease 'Stiff Person' Syndrome

By Stem Cell Treatment

TUESDAY, Aug. 26, 2014 (HealthDay News) -- Two women with a rare disorder called stiff person syndrome recovered after receiving transplants of their own stem cells, a study shows.

Stiff person syndrome is rare neurological disease that causes stiffness of the skeletal muscles and painful muscle spasms. In severe cases, the disorder makes it difficult to move or walk.

Both of the women were treated in Canada by a team led by Dr. Sheilagh Sanders of the University of Ottawa.

Stem cell transplantation using a patient's own cells has been used successfully in patients with autoimmune diseases such as multiple sclerosis and scleroderma, the team noted. The treatment involves eliminating diseased immune cells and then regenerating the immune system with a person's own stem cells.

One of the women described in the new report began developing stiff person syndrome in 2005 when she was 48, the researchers said. She began suffering from progressively stiffer legs, overactive reflexes and frequent falling. The woman also, "walked with an abnormal 'tin soldier' gait," the team said.

Despite the use of medication, her condition got so bad that by late 2008 she was forced to quit work and had become "socially withdrawn."

Hoping to help, Sanders and her colleagues treated the woman in 2009 with transplanted stem cells taken from the patient's own body.

One month after the procedure, the patient no longer had symptoms and six months after the transplant she had returned to work and was playing sports.

Nearly five years later, the woman is still symptom-free, the team said.

The other woman was diagnosed with stiff person syndrome in 2008 at age 30, and had frequent spasms triggered by cold weather or stress. In the year prior to her stem cell transplant, she "made 47 emergency medical services calls with subsequent hospital visits and had required intensive care unit admission," Sanders' team said.

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2 Cases Suggest Stem Cell Transplant Might Ease 'Stiff Person' Syndrome

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