NYU Langone Scientists Report Reliable and Highly Efficient Method for Making Stem Cells

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Newswise NEW YORK, September 18, 2014 Scientists at NYU Langone Medical Center have found a way to boost dramatically the efficiency of the process for turning adult cells into so-called pluripotent stem cells by combining three well-known compounds, including vitamin C.

Using the new technique in mice, the researchers increased the number of stem cells obtained from adult skin cells by more than 20-fold compared with the standard method. They say their technique is efficient and reliable, and thus should generally accelerate research aimed at using stem cells to generate virtually any tissue. Stem cells are immature or uncommitted cells that are theoretically capable of becoming any cell type.

This big boost in efficiency gives us an opportunity now to study stem cell programming mechanisms at high resolution, says Matthias Stadtfeld, PhD, assistant professor of cell biology and a member of the Skirball Institute of Biomolecular Medicine and the Helen L. and Martin S. Kimmel Center for Stem Cell Biology at NYU Langone Medical Center, who led the research.

This is a very exciting advance, says Ruth Lehmann, PhD, director of the Kimmel Center for Stem Cell Biology and the Skirball Institute at NYU Langone and chair of the Department of Cell Biology. The new technology developed by the Stadtfeld lab to reprogram differentiated cells efficiently and effectively brings the prospect of stem cell technology for safe use in regenerative medicine ever so much closer."

The standard method for reprogramming skin, blood, or other tissue-specific cell types into induced pluripotent stem cells (iPSCs) was reported in 2006 by the laboratory of Kyoto Universitys Shinya Yamanaka, who later won a Nobel Prize for the achievement. The method involves the artificial expression of four key genes dubbed OKSM (for Oct4, Klf4, Sox2 and myc) whose collective activity slowly prods cells into an immature state much like that of an early embryonic cell.

In principle, one could take a sample of cells from a person, induce the cells to become iPSCs, then multiply the iPSCs in a lab dish and stimulate them to mature towards desired adult cell types such as blood, brain or heartwhich then could be used to replace injured or diseased tissue in that same individual.

But there are many formidable technical obstacles, among which is the low efficiency of currently used protocols. Converting most cell types into stable iPSCs occurs at rates of 1 percent or less, and the process can take weeks.

Researchers throughout the world have been searching for ways to boost this efficiency, and in some cases have reported significant gains. These procedures, however, often alter vital cellular genes, which may cause problems for potential therapies. For the new study, reported online today in Stem Cell Reports, Dr. Stadtfeld and his laboratory team decided to take a less invasive approach and investigate chemical compounds that transiently modulate enzymes that are present in most cells. We especially wanted to know if these compounds could be combined to obtain stem cells at high efficiency, Dr. Stadtfeld says.

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NYU Langone Scientists Report Reliable and Highly Efficient Method for Making Stem Cells

Team reports reliable, highly efficient method for making stem cells

10 hours ago A new method resulted in a colony of stem cells, glowing green, derived from one adult immune cell. Credit: Laboratory of Matthias Stadtfeld at NYU Langone Medical center

Scientists at NYU Langone Medical Center have found a way to boost dramatically the efficiency of the process for turning adult cells into so-called pluripotent stem cells by combining three well-known compounds, including vitamin C. Using the new technique in mice, the researchers increased the number of stem cells obtained from adult skin cells by more than 20-fold compared with the standard method. They say their technique is efficient and reliable, and thus should generally accelerate research aimed at using stem cells to generate virtually any tissue. Stem cells are immature or uncommitted cells that are theoretically capable of becoming any cell type.

"This big boost in efficiency gives us an opportunity now to study stem cell programming mechanisms at high resolution," says Matthias Stadtfeld, PhD, assistant professor of cell biology and a member of the Skirball Institute of Biomolecular Medicine and the Helen L. and Martin S. Kimmel Center for Stem Cell Biology at NYU Langone Medical Center, who led the research.

"This is a very exciting advance," says Ruth Lehmann, PhD, director of the Kimmel Center for Stem Cell Biology and the Skirball Institute at NYU Langone and chair of the Department of Cell Biology. "The new technology developed by the Stadtfeld lab to reprogram differentiated cells efficiently and effectively brings the prospect of stem cell technology for safe use in regenerative medicine ever so much closer."

The standard method for reprogramming skin, blood, or other tissue-specific cell types into "induced pluripotent stem cells" (iPSCs) was reported in 2006 by the laboratory of Kyoto University's Shinya Yamanaka, who later won a Nobel Prize for the achievement. The method involves the artificial expression of four key genes dubbed OKSM (for Oct4, Klf4, Sox2 and myc) whose collective activity slowly prods cells into an immature state much like that of an early embryonic cell.

In principle, one could take a sample of cells from a person, induce the cells to become iPSCs, then multiply the iPSCs in a lab dish and stimulate them to mature towards desired adult cell types such as blood, brain or heartwhich then could be used to replace injured or diseased tissue in that same individual.

But there are many formidable technical obstacles, among which is the low efficiency of currently used protocols. Converting most cell types into stable iPSCs occurs at rates of 1 percent or less, and the process can take weeks.

Researchers throughout the world have been searching for ways to boost this efficiency, and in some cases have reported significant gains. These procedures, however, often alter vital cellular genes, which may cause problems for potential therapies. For the new study, reported online today in Stem Cell Reports, Dr. Stadtfeld and his laboratory team decided to take a less invasive approach and investigate chemical compounds that transiently modulate enzymes that are present in most cells. "We especially wanted to know if these compounds could be combined to obtain stem cells at high efficiency," Dr. Stadtfeld says.

Two of these compounds influence well known signaling pathways, called Wnt and TGF-, which regulate multiple growth-related processes in cells. The third is vitamin C (also known as ascorbic acid). Best known as a powerful antioxidant, the vitamin was recently discovered to assist in iPSC induction by activating enzymes that remodel chromatinthe spiral scaffold for DNAto regulate gene expression.

Simon Vidal, a graduate student in the Stadtfeld lab, and Bhishma Amlani, a postdoctoral researcher, looked first at mouse skin fibroblasts, the most common cell type used for iPSC research. Adding to fibroblasts engineered to express OKSM either vitamin C, a compound to activate Wnt signaling, or a compound to inhibit TGF- signaling increased iPSC-induction efficiency weakly to about 1% after a week of cell culture. Combining any two worked a bit better. But combining all three brought the efficiency to about 80 percent in the same period of time.

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Team reports reliable, highly efficient method for making stem cells

Stem cells use 'first aid kits' to repair damage

PUBLIC RELEASE DATE:

18-Sep-2014

Contact: Louise Walsh louise.walsh@admin.cam.ac.uk 44-012-237-65443 University of Cambridge @Cambridge_Uni

Stem cells hold great promise as a means of repairing cells in conditions such as multiple sclerosis, stroke or injuries of the spinal cord because they have the ability to develop into almost any cell type. Now, new research shows that stem cell therapy can also work through a mechanism other than cell replacement.

In a study published today in Molecular Cell, a team of researchers led by the University of Cambridge has shown that stem cells "communicate" with cells by transferring molecules via fluid filled bags called vesicles, helping other cells to modify the damaging immune response around them.

Although scientists have speculated that stem cells might act rather like drugs in sensing signals, moving to specific areas of the body and executing complex reactions this is the first time that a molecular mechanism for this process has been demonstrated. By understanding this process better, researchers can identify ways of maximising the efficiency of stem-cell-based therapies.

Dr Stefano Pluchino from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, who led the study, said: "These tiny vesicles in stem cells contain molecules like proteins and nucleic acids that stimulate the target cells and help them to survive they act like mini "first aid kits".

"Essentially, they mirror how the stem cells respond to an inflammatory environment like that seen during complex neural injuries and diseases, and they pass this ability on to the target cells. We think this helps injured brain cells to repair themselves."

Mice with damage to brain cells such as the damage seen in multiple sclerosis show a remarkable level of recovery when neural stem/precursor cells (NPCs) are injected into their circulatory system. It has been suggested that this happens because the NPCs discharge molecules that regulate the immune system and that ultimately reduce tissue damage or enhance tissue repair.

The team of researchers from the UK, Australia, Italy, China and Spain has now shown that NPCs make vesicles when they are in the vicinity of an immune response, and especially in response to a small protein, or cytokine, called Interferon-gamma which is released by immune cells. This protein has the ability to regulate both the immune responses and intrinsic brain repair programmes and can alter the function of cells by regulating the activity of scores of genes.

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Stem cells use 'first aid kits' to repair damage

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World Breakthrough: A New Molecule Allows for an Increase in Stem Cell Transplants

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Newswise Investigators from the Institute for Research in Immunology and Cancer (IRIC) at the Universit de Montral have just published, in the prestigious magazine Science, the announcement of the discovery of a new molecule, the first of its kind, which allows for the multiplication of stem cells in a unit of cord blood. Umbilical cord stem cells are used for transplants aimed at curing a number of blood-related diseases, including leukemia, myeloma and lymphoma. For many patients this therapy comprises a treatment of last resort.

Directed by Dr. Guy Sauvageau, principal investigator at IRIC and hematologist at the Maisonneuve-Rosemont Hospital, this world breakthrough has the potential to multiply by 10 the number of cord blood units available for a transplant in humans. In addition, it will considerably reduce the complications associated with stem cell transplantation. And it will be particularly useful for non-Caucasian patients for whom compatible donors are difficult to identify.

A clinical study using this molecule, named UM171 in honor of the Universit de Montral, and a new type of bioreactor developed for stem culture in collaboration with the University of Toronto will be initiated in December 2014 at the Maisonneuve-Rosemont Hospital.

According to Dr. Guy Sauvageau, This new molecule, combined with the new bioreactor technology, will allow thousands of patients around the world access to a safer stem cell transplant. Considering that many patients currently cannot benefit from a stem cell transplant for lack of matching donors, this discovery looks to be highly promising for the treatment of various types of cancer.

The Centre of Excellence for Cellular Therapy at the Maisonneuve-Rosemont Hospital will serve as production unit for these stem cells, and grafts will then be distributed to patients in Montreal, Quebec City and Vancouver for this first Canadian clinical study. Tangible results should be available one year later, that is, in December 2015. The significance of this new discovery is such that over time, conclusive clinical results could revolutionize the treatment of leukemia and other blood-related illnesses.

These extraordinary advances result from the efforts of a remarkable team that includes extremely gifted students and postdoctoral investigators working in the IRIC laboratories, adds Dr. Guy Sauvageau. Among them, the first authors of this publication: Iman Fars, doctoral student, and Jalila Chagraoui, research officer, along with the professionals in IRICs medical chemistry core facility under the direction of Anne Marinier, who optimized the therapeutic properties of this new molecule.

Context

Umbilical cord blood from newborn children is an excellent source of hematopoietic stem cells for stem cell transplants, since their immune system is still immature and the stem cells have a lower probability of inducing an adverse immune reaction in the recipient.

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World Breakthrough: A New Molecule Allows for an Increase in Stem Cell Transplants

Stem cell revolution gets closer

Edgar Irastorza was just 31 when his heart stopped beating in October 2008.

A Miami property manager, Irastorza had recently gained weight as his wife's third pregnancy progressed. "I kind of got pregnant, too," he said.

During a workout one day, he felt short of breath and insisted that friends rush him to the hospital. Minutes later, his pulse flatlined. He survived the heart attack, but the scar tissue that resulted cut his heart's pumping ability by a third. He couldn't pick up his children. He fell asleep every night wondering if he would wake up in the morning.

Desperation motivated Irastorza to volunteer for a highly unusual medical research trial: getting stem cells injected directly into his heart. "I just trusted my doctors and the science behind it, and said, 'This is my only chance,' " he said recently.

Over the last five years, by studying stem cells in lab dishes, test animals and intrepid patients like Irastorza, researchers have brought the vague, grandiose promises of stem cell therapies closer to reality.

Stem cells broke into the public consciousness in the early 1990s, alluring for their potential to help the body beat back diseases of degeneration like Alzheimer's, and to grow new parts to treat conditions like spinal cord injuries.

Progress has been slow. But researchers are learning how to best use stem cells, what types to use and how to deliver them to the body findings that are not singularly transformational, but progressive and pragmatic.

As many as 4,500 clinical trials involving stem cells are under way in the United States to treat patients with heart disease, blindness, Parkinson's, HIV, blood cancers and spinal cord injuries, among other conditions.

Initial studies suggest that stem cell therapy can be delivered safely, said Dr. Ellen Feigal, senior vice president of research and development at the California Institute of Regenerative Medicine, the state stem cell agency, which has awarded more than $2 billion toward stem cell research since 2006.

But enthusiasm for stem cells sometimes outstrips the science. When Gov. Rick Perry of Texas had adult stem cells injected into his spine in 2011 for a back injury, his surgeon had never tried the procedure and had no data to support the experiment. A June review in the New England Journal of Medicine found that "platelet-rich plasma" stem cell therapies praised by a number of athletes worked no better than placebos.

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Stem cell revolution gets closer

21 infused with new UM stem cell

Written by Lidia Dinkova on September 17, 2014

A partnership between University of Miami researchers and a Georgia-based biomedical company this month made a new type of stem cell commercially available for bone regeneration and healing.

The marrow-isolated adult multi-lineage inducible cell, known as the MIAMI cell, is the result of 15 years of research by the University of Miami.

Since the stem cell was made commercially available, about 21 patients have been treated with a MIAMI cell infusion.

We are controlling the release to make sure it goes very smoothly, said Tracy S. Anderson, president and CEO of Vivex Biomedical Inc.

Vivex invested in the research and development of the cell and licensed the technology from UM for orthopedic use. The company has contracted with the universitys tissue bank to develop the cell for commercial use and pays an undisclosed royalty back to UM from sales.

Before the MIAMI cell goes to full national release in January 2015, Vivex is controlling the use of the cell.

I am going very slowly and selectively with the surgeons we are working with, Mr. Anderson said. Anytime you have a new product like this, you have to make sure that it goes smoothly.

Mr. Anderson didnt want to disclose revenue generated from the sale of the MIAMI cell, only saying that it has been significant.

So far, the MIAMI cell has been used in bone regeneration and healing in Utah, Florida, Georgia, Michigan, Illinois and Ohio.

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21 infused with new UM stem cell

Building the Sanford Stem Cell Clinical Center Inpatient Facility at the Jacobs Medical Center – Video


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Stem cell harvesting methods used by Sydney doctor Ralph Bright untested by clinical trials

ABC Ralph Bright harvests stem cells using the liposuction.

Serious questions have been raised about a stem cell doctor working in Western Sydney who charges $9,000 per procedure and uses methods that are untested by clinical trials.

An investigation by the ABC's 7.30 program has revealed that Dr Ralph Bright bought his liposuction-based technology from an American company.

The US company is now the subject of a multi-million dollar fraud action, which has revealed the cells being marketed as live were in fact dead.

Dr Bright, of Macquarie Stem Cells, is a former GP and self-taught cosmetic surgeon.

He has been working with stem cells for four years, treating more than 400 patients, including the late model Charlotte Dawson, cricketer Geoff Lawson and Olympic volleyballer Kerri Pottharst.

Dr Bright has licensed his methods to other practitioners around the country and because they use the patients' own cells he is not regulated by the Therapeutic Goods Administration (TGA).

Stem cells are often hailed as a miracle cure, but the nation's top stem cell scientists are warning that buyers should beware of these sorts of procedures, which are yet to be subjected to clinical trials.

Professor of Stem Cell Science at the University of Melbourne, Martin Pera, said almost all stem cell therapy was experimental.

"Actually, this whole science of cell therapy is relatively new and it's very, very important to understand that," he said.

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Stem cell harvesting methods used by Sydney doctor Ralph Bright untested by clinical trials

Stem cells treatment used by Sydney doctor Ralph Bright 'untested' by clinical trials

ABC Ralph Bright harvests stem cells using the liposuction.

Serious questions have been raised about a stem cell doctor working in Western Sydney who charges $9,000 per procedure and uses methods that are untested by clinical trials.

An investigation by the ABC's 7.30 program has revealed that Dr Ralph Bright bought his liposuction-based technology from an American company.

The US company is now the subject of a multi-million dollar fraud action, which has revealed the cells being marketed as live were in fact dead.

Dr Bright, of Macquarie Stem Cells, is a former GP and self-taught cosmetic surgeon.

He has been working with stem cells for four years, treating more than 400 patients, including the late model Charlotte Dawson, cricketer Geoff Lawson and Olympic volleyballer Kerri Pottharst.

Dr Bright has licensed his methods to other practitioners around the country and because they use the patients' own cells he is not regulated by the Therapeutic Goods Administration (TGA).

Stem cells are often hailed as a miracle cure, but the nation's top stem cell scientists are warning that buyers should beware of these sorts of procedures, which are yet to be subjected to clinical trials.

Professor of Stem Cell Science at the University of Melbourne, Martin Pera, said almost all stem cell therapy was experimental.

"Actually, this whole science of cell therapy is relatively new and it's very, very important to understand that," he said.

Read more:
Stem cells treatment used by Sydney doctor Ralph Bright 'untested' by clinical trials