Stem Cell Clinic

Mechanical cues reprogram normal cell lines into stem-like cells

By Uncategorized

Scientists at UB and other institutions have turned cells normally used as model cells, known as immortalized cells, into stem or, as they call it, stem-like cells, using nothing more than mechanical stress. They have done it without employing the potentially hazardous techniques previously used to obtain similar results.

The researchers use the term stem-like cells to describe cells in tissue culture that have many of the biochemical markers of stem cells. Determining whether or not they can differentiate will be the focus of future research.

The finding is described in a paper published recently online before print in the Proceedings of the National Academy of Sciences. The researchers discovered that changing the mechanical stresses on neuronal and other cell types in tissue culture allowed them to be reprogrammed into stem-like cells.

Normal cell types in tissue culture are spread out and have differentiated internal structures, but changing cell mechanics caused the cells to turn into clusters of spherical cells that had many of the biochemical markers of cells, says Frederick Sachs, SUNY Distinguished Professor in the Department of Physiology and Biophysics and senior author.

The stem cell advance was made possible by the development of a genetically encoded optical probe by Fanje Meng, research assistant professor in the Department of Physiology and Biophysics and lead UB author. The probe measures the mechanical stress in actin, a major structural protein present in all cells. Actin is involved in muscle contraction and numerous cellular processes, including cell signaling, how cells are shaped and how they move.

The actin probes will provide researchers with a method of studying how mechanical forces influence living cells, tissues, organs and animals in real time.

This probe allows us, for the first time, to measure the stress in actin within living cells, explains Sachs. We saw gradients of stress in actin filaments even in single living cells.

Much of existing biomechanics will have to be rethought, since many studies have assumed that the stresses are uniform, Sachs continues. The actin stress probe showed that the tension in actin fibers in stem cells is higher than in normal cells. That was very surprising to us.

He adds that while mechanics are well known to have a role in cellular processes, the details are poorly understood because there have been few ways to measure the stress in specific proteins. A clinically relevant example is that metastatic cancer cells, the fatal variety, have different mechanics than cells of the parent tumor.

This probe will allow cancer researchers to better understand what allows cells to become metastatic, says Sachs.

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Mechanical cues reprogram normal cell lines into stem-like cells

Canadian-led team of researchers shows how stem cells can be reprogrammed

By Stem Cell Treatment

TORONTO A Canadian-led international team of researchers has begun solving the mystery of just how a specialized cell taken from a persons skin is reprogrammed into an embryonic-like stem cell, from which virtually any other cell type in the body can be generated.

The research is being touted as a breakthrough in regenerative medicine that will allow scientists to one day harness stem cells to treat or even cure a host of conditions, from blindness and Parkinsons disease to diabetes and spinal cord injuries.

Besides creating the reprogramming roadmap, the scientists also identified a new type of stem cell, called an F-class stem cell due to its fuzzy appearance. Their work is detailed in five papers published Wednesday in the prestigious journals Nature and Nature Communications.

Dr. Andras Nagy, a senior scientist at Mount Sinai Hospital in Toronto, led the team of 50 researchers from Canada, the Netherlands, South Korea and Australia, which spent four years analyzing and cataloguing the day-by-day process that occurs in stem cell reprogramming.

The work builds on the 2006-2007 papers by Shinya Yamanaka, who showed that adult skin cells could be turned into embryonic-like, or pluripotent, stem cells through genetic manipulation, a discovery that garnered the Japanese scientist the Nobel Prize in 2012.

Nagy likened the roughly 21-day process to complete that transformation to a black box, so called because scientists did not know what went on within the cells as they morphed from one cell type into the other.

It was just like a black box, Nagy said Wednesday, following a briefing at the hospital. You start with a skin cell, you arrive at a stem cell but we had no idea what was happening inside the cell.

Nagys team set about cataloguing the changes as they occurred by removing cells from culture dishes at set points during the three-week period, then analyzing such cellular material as DNA and proteins present at that moment.

The result is a database that will be available to scientists around the world, which the team hopes will spur new research to advance the field of stem cell-based regenerative medicine.

Co-author Ian Rogers, a scientist in Nagys lab, said the database will allow researchers to identify various properties of the developing stem cells, which could mean improving their ability to treat or cure disease.

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Canadian-led team of researchers shows how stem cells can be reprogrammed

Researchers discover new class of stem cells

By Stem Cell Medicine

Researchers have identified a new class of lab-engineered stem cells -- cells capable of transforming into nearly all forms of tissue -- and have dubbed them F-class cells because they cluster together in "fuzzy-looking" colonies.

The discovery, which was described in a series of five papers published Wednesday in the journals Nature and Nature Communications, sheds new light on the process of cell reprogramming and may point the way to more efficient methods of creating stem cells, researchers say.

Due to their extraordinary shape-shifting abilities, so-called pluripotent cells have enormous value to medical researchers. They allow scientists to study the effects of drugs and disease on human cells when experiments on actual people would be impossible, and they have given rise to the field of regenerative medicine, which seeks to restore lost or damaged organs and tissues.

The F-class cells were created using genetically engineered mouse cells, and may not occur naturally outside the lab, according to senior author Andras Nagy, a stem cell researcher at Torontos Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital.

However, the find suggests that there may be other classes of pluripotent cells -- or a spectrum of reprogrammed cells -- yet to be discovered, authors say.

We think that if we have time, and money and hands to do it, we might find additional novel cell lines, Nagy said.

Until now, stem cells have been either obtained from embryos or produced in the lab through a painstaking process called induced pluripotency, whereby a virus is used to alter an adult cells genetic information and return the cell to a pliable, embryonic state.

That process, which was pioneered by Dr. Shinya Yamanaka and recognized with the Nobel Prize in Physiology or Medicine in 2012, is extremely inefficient, yielding embryonic-stem-cell-like cells just 1% of the time.

Nagy and his colleagues, a consortium of international researchers called Project Grandiose, began their research by looking more closely at the castoffs of that process, or those cells that did not closely match the description of embryonic stem cells.

We looked at it in an unbiased way, Nagy said. Instead of ignoring or discarding those cells that dont look like embryonic stem cells, we thought we might find more than just one alternative cell type.

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Researchers discover new class of stem cells

Stem cell discovery could lead to hair loss treatments

By Stem Cell Medicine

CALGARY New research from the University of Calgary may hold the key to restoring hair growth.

The findings, published in the scientific journal Developmental Cell this week, identify the existence of a skin stem cell in adult hair follicles that may one day be targeted to stimulate new hair growth after injury, burns, disease or aging.

The discovery is being called an important a step towards new hair loss treatments.

We hope that we can ultimately stimulate these cells with drugs to replenish or rejuvenate the cells that are responsible for inducing hair growth, says assistant professor in stem cell biology at the Faculty of Veterinary Medicine Jeff Biernaskie, PhD.

Hair follicles undergo a constant cycle of regeneration and degeneration, and Biernaskie wanted to identify the stem cells that oversee that cycle.

Biernaskies team discovered that a small number of dermal sheath cells could self-renew, and gave rise to hundreds of new cells in each hair follicle.

He says the discovery gives researchers a greater understanding of how hair follicles regenerate and it opens the door to creating therapies targeting stem cells to restore hair growth.

However, it could be a decade before such therapies are developed.

Biernaskies research holds hope for animals as well as humans.

Animals suffer skin diseases and injuries similar to people, and he says anything that improves the understanding of stem cells in healing and regeneration in people is also applicable to healing in animals.

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Stem cell discovery could lead to hair loss treatments

New UQ platform aids stem cell research

By Stem Cell Medicine

Researchers at The University of Queensland are part of a global team that has identified a new type of artificial stem cell.

UQ Associate Professor Christine Wells (right) said Project Grandiose had revealed it could track new ways to reprogram a normal adult cell, such as skin cells, into cells similar to those found in an early embryo.

The development is expected to help researchers explore ways to arrive at new cell types in the laboratory, with important implications for regenerative medicine and stem cell science.

Associate Professor Wells, who leads the Stemformatics stem cell research support unit at UQs Australian Institute for Bioengineering and Nanotechnology, said the project involved a consortium of 50 researchers from Canada, Australia, Korea, the USA and the Netherlands

We all come from just one cell the fertilised egg and this cell contains within its DNA a series of instruction manuals to make all of the many different types of cells that make up our body, AIBN Associate Professor Wells said.

These very early stage cells can now be made in the lab by reversing this process of development.

Our research reveals the new instructions imposed on a cell when this developmental process is reversed.

Project Grandiose is a large-scale research effort to understand what happens inside a cell as it reverts to an artificial stem cell.

The role of the Stemformatics.org group was to help the researchers have access to the vast information and data they generated from the project, Associate Professor Wells said.

Our online data platform is designed to let non-specialists view the genes involved and the many ways they are regulated during cell formation.

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New UQ platform aids stem cell research

NYSCF and the CMTA enter collaboration to advance neuropathies research

By Stem Cell Medical Center

PUBLIC RELEASE DATE:

10-Dec-2014

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

New York, NY (December 10, 2014) - The New York Stem Cell Foundation (NYSCF) Research Institute, a non-profit organization dedicated to accelerating cures through stem cell research, announced a collaboration today with the Charcot-Marie-Tooth Association (CMTA), a patient-led disease foundation with the mission to advance research on genetic neuropathies that leads to the development of new therapies. The immediate aim of the collaboration is to develop a bank of induced pluripotent stem cell (iPSC) lines for a variety of neuropathy disorders of known genetic causation and to eventually develop personalized drug therapies.

NYSCF will make stem cells lines from Charcot-Marie-Tooth patient materials that have been curated in a biobank assembled by Dr. Michael Shy at the University of Iowa, a member of the CMTA STAR consortium of sponsored investigators. Utilizing its automated technology, the NYSCF Global Stem Cell ArrayTM, NYSCF will systematically generate iPSC lines from tissue samples obtained from patients representing a number of disease states. These cell lines will then be used to develop methods for creating differentiated cells that mimic the myelin-producing Schwann cells that are defective in Type 1 Charcot-Marie-Tooth (CMT) disorders of peripheral nerve, as well as the motor and sensory neurons that are defective in Type 2 disorders. Members of the STAR consortium currently engaged in this CMTA-sponsored effort to differentiate iPSC lines include Dr. Robert Baloh, Cedar-Sinai Medical Center, and Dr. Gabsang Lee, Johns Hopkins University. The ultimate aim of this research is to create a personalized medicine approach to rapid testing of human drug responsiveness in a dish. The iPSC lines will also be expanded and banked by NYSCF and made available to the global scientific community to be used for research and the development of therapies.

Patrick Livney, CEO of the CMTA notes: "The Foundation has assembled the scientific and clinical key opinion leaders in CMT disorders, and the research tools necessary to validate therapeutic opportunities for their clinical potential. We have set out to engage drug makers to work together with the CMTA to advance new therapeutic approaches to our patients, and our STAR network that combines this world class research expertise with an operational capability has been highly enabling to the formation of collaborative alliances for this purpose. Currently, there are no therapies for the different CMT disorders to halt either the onset or progression of the disease. This NYSCF collaboration represents an exciting opportunity for the CMTA to place research on therapies for Charcot-Marie-Tooth disorders in a personalized, patient context at a very early stage.

"We are very exctied to partner with the Charcot-Marie-Tooth Association to develop resources that will enable the pursuit of new treatments and eventually cures for neruropathy disorders," said Susan L. Solomon, Co-Founder and CEO of NYSCF. "Partnering with CMTA provides us with the necessary community of scientists, patients, disease experts, as well as resources that allows us to move research forward. We believe that this type of interdisciplinary collaboration between various stakeholders is essential to to move research forward in the pursuit of cures."

###

About Charcot-Marie-Tooth Association

The Charcot-Marie-Tooth Association (CMTA) is a registered 501c3 dedicated to serving an international patient community that suffers from rare and disabling neuropathies of genetic origin. The Foundation directly engages its STAR scientific and clinical research network in the identification, validation and clinical development of therapies for the different Charcot-Marie-Tooth disorders.

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NYSCF and the CMTA enter collaboration to advance neuropathies research

Canadian scientists crack stem cell reprogramming code

By Stem Cell Medical Center

By Sheryl Ubelacker The Canadian Press

WATCH: Dr. Andras Nagy describes the scientific breakthrough he led in solving the mystery of the stem cell reprogramming code.

TORONTO A Canadian-led international team of researchers has begun solving the mystery of just how a specialized cell taken from a persons skin is reprogrammed into an embryonic-like stem cell, from which virtually any other cell type in the body can be generated.

The research is being touted as a breakthrough in regenerative medicine that will allow scientists to one day harness stem cells to treat or even cure a host of conditions, from blindness and Parkinsons disease to diabetes and spinal cord injuries.

Besides creating the reprogramming roadmap, the scientists also identified a new type of stem cell, called an F-class stem cell due to its fuzzy appearance. Their work is detailed in five papers published Wednesday in the prestigious journals Nature and Nature Communications.

Dr. Andras Nagy, a senior scientist at Mount Sinai Hospital in Toronto, led the team of 50 researchers from Canada, the Netherlands, South Korea and Australia, which spent four years analyzing and cataloguing the day-by-day process that occurs in stem cell reprogramming.

The work builds on the 2006-2007 papers by Shinya Yamanaka, who showed that adult skin cells could be turned into embryonic-like, or pluripotent, stem cells through genetic manipulation, a discovery that garnered the Japanese scientist the Nobel Prize in 2012.

Nagy likened the roughly 21-day process to complete that transformation to a black box, so called because scientists did not know what went on within the cells as they morphed from one cell type into the other.

It was just like a black box, Nagy said Wednesday, following a briefing at the hospital. You start with a skin cell, you arrive at a stem cell but we had no idea what was happening inside the cell.

Nagys team set about cataloguing the changes as they occurred by removing cells from culture dishes at set points during the three-week period, then analyzing such cellular material as DNA and proteins present at that moment.

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Canadian scientists crack stem cell reprogramming code

Stem cells: The black box of reprogramming

By Stem Cell Clinic

Nik Spencer/Nature

Eggs and sperm do it when they combine to make an embryo. John Gurdon did it in the 1960s, when he used intestinal cells from tadpoles to generate genetically identical frogs. Ian Wilmut did it too, when he used an adult mammalian cell to make Dolly the sheep in 1996. Reprogramming reverting differentiated cells back to an embryonic state, with the extraordinary ability to create all the cells in the body has been going on for a very long time.

Scientific interest in reprogramming rocketed after 2006, when scientists showed that adult mouse cells could be reprogrammed by the introduction of just four genes, creating what they called induced pluripotent stem (iPS) cells1. The method was simple enough for almost any lab to attempt, and now it accounts for more than a thousand papers per year. The hope is that pluripotent cells could be used to repair damaged or diseased tissue something that moved closer to reality this year, when retinal cells derived from iPS cells were transplanted into a woman with eye disease, marking the first time that reprogrammed cells were transplanted into humans (see Nature http://doi.org/xhz; 2004).

There is just one hitch. No one, not even the dozen or so groups of scientists who intensively study reprogramming, knows how it happens. They understand that differentiated cells go in, and pluripotent cells come out the other end, but what happens in between is one of biology's impenetrable black boxes. We're throwing everything we've got at it, says molecular biologist Knut Woltjen of the Center for iPS Cell Research and Application at Kyoto University in Japan. It's still a really confusing process. It's very complicated, what we're doing.

Kerri Smith talks to researcher Andras Nagy and reporter David Cyranoski about reprogramming cells.

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One of the problems, stem-cell biologists say, is that their starting population contains a mix of cells, each in a slightly different molecular state. And the process for making iPS cells is currently inefficient and variable: only a tiny fraction end up fully reprogrammed and even these may differ from one another in subtle but important ways. What is more, the path to reprogramming may vary depending on the conditions under which cells are being grown, and from one lab to the next. This makes it difficult to compare experimental results, and it raises safety concerns should a mix of poorly characterized cells be used in the clinic.

But new techniques are starting to clarify the picture. By carrying out meticulous analyses of single cells and amassing reams of detailed molecular data, biologists are identifying a number of essential events that take place en route to a reprogrammed state. This week, the biggest such project an international collaboration audaciously called Project Grandiose unveiled its results26. The scientists involved used a battery of tests to take fine-scale snapshots of every stage of reprogramming and in the process, revealed an alternative state of pluripotency. It was the first high-resolution analysis of change in cell state over time, says Andras Nagy, a stem-cell biologist at Mount Sinai Hospital in Toronto, Canada, who led the project. I'm not shy about saying grandiose.

I'm not shy about saying grandiose.

But there is more to do if scientists want to control the process well enough to generate therapeutic cells with ease. Yes, we can make iPS cells and yes we can differentiate them, but I think we feel that we do not control them enough says Jacob Hanna, a stem-cell biologist at the Weizmann Institute of Science in Rehovot, Israel. Controlling cell behaviour at will is very cool. And the way to do it is to understand their molecular biology with great detail.

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Stem cells: The black box of reprogramming

The NFL Has a Problem with Stem Cell Treatments

By Stem Cell Treatment

Professional athletes are getting injections of stem cells to speed up recovery from injury. Critics call it a high-tech placebo.

NFL quarterback Peyton Manning reportedly had a stem cell treatment to his neck in 2011.

Elite athletes do whatever it takes to win. Lately, thats meant getting an injection of their own stem cells.

The treatments, developed over the last eight years, typically involve extracting a small amount of a players fat or bone marrow and then injecting it into an injured joint or a strained tendon to encourage tissue regeneration. Bone marrow contains stem cells capable of generating new blood cells, cartilage, and bone.

Although the treatments have become a multimillion-dollar industry, some doctors say theres only thin medical evidence they actually speed healing. In a report issued last week, public policy researchers at Rice University criticized the National Football Leagues role in promoting unproven treatments to the public. Some players, including Peyton Manning of the Denver Broncos and Sidney Rice, whos now retired but won a Super Bowl with the Seattle Seahawks last year, have reportedly gone overseas for stem cell treatments and others have acted as spokespeople for U.S. clinics offering them.

The Rice researchers, Kirstin Matthews and Maude Cuchiara, say the NFL should create an independent panel and fund research on whether stem cell treatments actually work, similar to what it did after facing questions around concussions and brain injury. I think they should be more proactive. They should get ahead of this one, says Matthews.

Sports Illustrated reports that hundreds of football players have gotten stem cell treatments, with many travelling abroad for types of therapy not offered in the United States.But its not only football players trying them. The tennis player Rafael Nadal is reportedly undergoing stem cell treatments for back pain, and the injections are also being sought out by soccer players and high school athletes.

The NFL didnt respond to questions from MIT Technology Review. Doctors offering the treatments say theyre promising and should be given a chance. Others say theres not enough data. Any of these injections have a placebo effect, says Freddie Fu, an orthopedic surgeon who is chairman of sports medicine at the University of Pittsburgh Medical Center and top doctor for the schools sports teams. We dont know what we are putting in. We dont really know what exactly what it does, biologically.

Orthopedic surgeons hope one day to use stem cells to regenerate cartilage and other lost tissue. But wishful thinking, and profits, have gotten ahead of the facts, says Fu. Theres a lot of marketing in orthopedics right now. I would say 15 to 20 percent of treatments are not effective, he says.

Unlike a drug, which gets tested for years and is then weighed by experts and the U.S. Food and Drug Administration before hitting the market, the bone marrow treatments offered in the U.S. arent regulated.

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The NFL Has a Problem with Stem Cell Treatments

This New Kind of Stem Cell May Revolutionize How We Treat Diseases

By Stem Cell Treatment

TIME Health medicine This New Kind of Stem Cell May Revolutionize How We Treat Diseases Scientists have created a new type of stem cell that could speed treatments for diseases and make them safer

Ever since Japanese researcher Shinya Yamanaka found a way to treat skin cells with four genes and reprogram them back to their embryonic state, scientists have been buzzing over the promise of stem cell therapies. Stem cells can be coaxed to become any of the bodys cell types, so they could potentially replace diseased or missing cells in conditions such as diabetes or Alzheimers. And Yamanakas method also meant that these cells could be made from patients themselves, so they wouldnt trigger dangerous immune rejections.

Now scientists led by Dr. Andras Nagy at Mount Sinai Hospital Lunenfeld-Tannenbaum Research Institute in Toronto report an exciting new advance that could push stem cells even closer to the clinic. In a series of papers in the journals Nature and Nature Communications, the group describes a new class of stem cell, which they called F class, that they generated in the lab.

The F class cells, says Nagy, have a few advantages over the Yamanaka-generated induced pluripotent stem cells, or iPS cells. While the iPS cells are created by using viruses to introduce four genes that reprogram the cells, Nagys team relied on a technique they developed several years ago using transposonssmall pieces of DNA that can insert themselves into different parts of a genome. Unlike viruses, these transposons can be popped out of the genome if theyre no longer needed, and they dont carry the potential risk of viral infection.

MORE: Stem-Cell Research: The Quest Resumes

Nagys team found that the transposons were much more reliable vehicles for delivering the reprogramming genes exactly where they were needed to efficiently turn the clock back on the skin cells. Whats more, they could use the common antibiotic doxycycline to turn the four genes on and off; adding doxycycline to the cell culture would trigger the transposons to activate, thus turning on the genes, while removing the antibiotic would turn them off.

In this way, says Nagy, he was able to pump up the efficiency of the reprogramming process. Using the Yamanaka method, it was hit-or-miss whether the viruses would find their proper place in a cells genome, and more uncertainty over how effectively it could direct the cell to activate the four reprogramming genes. F class cells are much more similar [in the culture dish], like monozygotic twins while iPS cells are more like brothers and sisters, he says.

That consistency is a potential advantage of the transposon method, since any stem cell-based treatment would require a robust population of stem cells which can then be treated with the proper compounds to develop into insulin-making pancreatic cells to treat diabetes, or new nerve cells to replace dying ones in Alzheimers, or fresh heart muscle to substitute for scarred tissue after a heart attack.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimers

Nagys team also described, with the most detail to date, exactly how mature cells like skin cells perform the ultimate molecular feat and become forever young again when exposed to the four genes. They analyzed the changes in the cells DNA, the proteins they made, and more. Its similar to high definition TV, he says. We see things much better with much more detail. We expect that having that high resolution characterization will allow us to better understand what is happening during this process at the molecular level. And obviously that better understanding is going to affect what we can do with these cells to make them better, safer and more efficient in cell-based treatments in the future.

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This New Kind of Stem Cell May Revolutionize How We Treat Diseases

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