Exercise triggers stem cells in muscle

University of Illinois researchers determined that an adult stem cell present in muscle is responsive to exercise, a discovery that may provide a link between exercise and muscle health. The findings could lead to new therapeutic techniques using these cells to rehabilitate injured muscle and prevent or restore muscle loss with age.

13 feb 2012--Mesenchymal stem cells (MSCs) in skeletal muscle have been known to be important for muscle repair in response to non-physiological injury, predominantly in response to chemical injections that significantly damage muscle tissue and induce inflammation. The researchers, led by kinesiology and community health professor Marni Boppart, investigated whether MSCs also responded to strain during exercise, and if so, how.

"Since exercise can induce some injury as part of the remodeling process following mechanical strain, we wondered if MSC accumulation was a natural response to exercise and whether these cells contributed to the beneficial regeneration and growth process that occurs post-exercise," said Boppart, who also is affiliated with the Beckman Institute for Advanced Science and Technology at the U. of I.

The researchers found that MSCs in muscle are very responsive to mechanical strain. They witnessed MSC accumulation in muscle of mice after vigorous exercise. Then, they determined that although MSCs don't directly contribute to building new muscle fibers, they release growth factors that spur other cells in muscle to fuse and generate new muscle, providing the cellular basis for enhanced muscle health following exercise.

A key element to the Illinois team's method was in exercising the mice before isolating the cells to trigger secretion of beneficial growth factors. Then, they dyed the cells with a fluorescent marker and injected them into other mice to6 see how MSCs coordinated with other muscle-building cells.

In addition to examining the cells in vivo, the researchers studied the cells' response to strain on different substrates. They found that MSC response is very sensitive to the mechanical environment, indicating that conditions of muscle strain affect the cells' activity.

"These findings are important because we've identified an adult stem cell in muscle that may provide the basis for muscle health with exercise and enhanced muscle healing with rehabilitation/movement therapy," Boppart said. "The fact that MSCs in muscle have the potential to release high concentrations of growth factor into the circulatory system during exercise also makes us wonder if they provide a critical link between enhanced whole-body health and participation in routine physical activity."

Next, the group hopes to determine whether these cells contribute to the decline in muscle mass over a person's lifetime. Preliminary data suggest MSCs become deficient in muscle with age. The team hopes to develop a combinatorial therapy that utilizes molecular and stem-cell-based strategies to prevent age-related muscle loss.

"Although exercise is the best strategy for preserving muscle as we age, some individuals are just not able to effectively engage in physical activity," Boppart said. "Disabilities can limit opportunities for muscle growth. We're working hard to understand how we can best utilize these cells effectively to preserve muscle mass in the face of atrophy."

The team published its findings in the journal PLoS One. The Illinois Regenerative Medicine Institute, the Ellison Medical Foundation and the Mary Jane Neer Foundation supported this work.

More information: The paper, "Eccentric Exercise Facilitates Mesenchymal Stem Cell Appearance in Skeletal Muscle," is available online on PLoS ONE site.

Provided by University of Illinois at Urbana-Champaign

Man Who Helped Start Stem Cell War May End It

By GINA KOLATA
If the stem cell wars are indeed nearly over, no one will savor the peace more than James A. Thomson.
Dr. Thomson’s laboratory at the University of Wisconsin was one of two that in 1998 plucked stem cells from human embryos for the first time, destroying the embryos in the process and touching off a divisive national debate.
And on Tuesday, his laboratory was one of two that reported a new way to turn ordinary human skin cells into what appear to be embryonic stem cells without ever using a human embryo.
The fact is, Dr. Thomson said in an interview, he had ethical concerns about embryonic research from the outset, even though he knew that such research offered insights into human development and the potential for powerful new treatments for disease.
“If human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough,” he said. “I thought long and hard about whether I would do it.”
He decided in the end to go ahead, reasoning that the work was important and that he was using embryos from fertility clinics that would have been destroyed otherwise. The couples whose sperm and eggs were used to create the embryos had said they no longer wanted them. Nonetheless, Dr. Thomson said, announcing that he had obtained human embryonic stem cells was “scary,” adding, “It was not known how it would be received.”
But he never anticipated the extent and rancor of the stem cell debate. For nearly a decade now, the issue has bitterly divided patients and politicians, religious groups and researchers.
Now with the new technique, which involves adding just four genes to ordinary adult skin cells, it will not be long, he says, before the stem cell wars are a distant memory. “A decade from now, this will be just a funny historical footnote,” Dr. Thomson said in the interview.
As for the science behind it, the thrill of discovery, he said, “Surprisingly, there is no ‘Wow’ moment,” either from 1998 or now. Both times, the discovery came after he had spent months rigorously testing the cells to be sure they really were stem cells, worrying all the while that they could die or be lost to contamination. When he knew he had succeeded, the suspense was gone.
“Imagine holding your breath for a few months,” Dr. Thomson said. When he was done, he said, “I felt mostly a sense of relief.”
But he knows what he wrought. Stem cells, universal cells that can turn into any of the body’s 220 cell types, normally emerge only fleetingly after a few days of embryo development. Scientists want to use them to study complex human diseases like Alzheimer’s or Parkinson’s in a petri dish, finding causes and treatments. And, they say, it may be possible to use the cells to grow replacement tissues for patients.
The problem until now had been the source of the cells — human embryos.
The topic, says R. Alta Charo, a University of Wisconsin ethicist, “took on an almost iconic quality the same way Roe v. Wade has.”
In the meantime, many leading scientists decided not to get into the stem cell field. There was a stigma attached, Dr. Thomson says. And, he adds, “Most scientists don’t like controversial things.”
A native of Oak Park, Ill., James Alexander Thomson, 48, did not set out to throw bioethical bombs. All he wanted, he said, was to answer the most basic scientific questions about cellular development.
First there was a degree in biophysics from the University of Illinois. As a graduate student, Dr. Thomson began working with mouse embryonic stem cells and then, with federal support, he extracted stem cells from monkey embryos. After earning two doctorates from the University of Pennsylvania, one in veterinary medicine and one in molecular biology, he continued research at his own laboratory at the University of Wisconsin.
Eventually he realized, though, that studying mice and monkeys could take him only so far. If he wanted to understand how human embryos develop and why their development sometimes goes awry, he needed human stem cells. But, he says, he hesitated.
In 1995, he began consulting with two ethicists at his university, Dr. Norman Fost, a physician, and Ms. Charo, a law professor. He wanted to anticipate what the ethical problems might be and what the criticisms might be.
Dr. Fost was impressed.
“It is unusual in the history of science for a scientist to really want to think carefully about the ethical implications of his work before he sets out to do it,” Dr. Fost said. “The biggest problem in ethics is not anticipating problems.”
But Dr. Fost and Dr. Thomson guessed wrong about what would bother people most. They thought it would be what Dr. Fost termed “the technological power” of stem cells. What if someone put human stem cells into the brain of a rat, for example?
“I thought at the time that this was possibly the biggest issue,” Dr. Fost said. “It was unprecedented in the history of biology. It’s the ‘Help, get me out of here’ scenario. Let’s say the rat brain turns out to be entirely human cells. What’s going on in there? Is it a human brain? And how would you study it — you can’t ask the rat.”
Meanwhile, as Dr. Thomson was planning his effort to obtain human embryonic stem cells, another discovery changed his entire view of development. In 1997, Ian Wilmut, a scientist in Scotland, announced the creation of the first cloned mammal, Dolly, cloned from frozen udder cells from a long-dead sheep.
Dr. Wilmut had slipped an udder cell — a cell that normally would never be anything but an udder cell — into an egg whose genetic material had been removed. The egg somehow brought the udder cell’s chromosomes back to the state they had been in when embryo development first began.
“Dolly changed the way I thought about developmental biology,” Dr. Thomson says. “Development was reversible.”
Four years ago he and, independently, Shinya Yamanaka of Kyoto University set out to figure out a way to mimic what an egg can do. Both succeeded and both discovered that all they had to do was add four genes to the cells and the cells would turn into what look, so far, just like stem cells.
“It is actually fairly straightforward to repeat what we have done,” Dr. Thomson said.
More work remains, but he is confident that the path ahead is clear.
“Isn’t it great to start a field and then to end it,” he said.

Stem cell breakthrough defuses debate

By MALCOLM RITTER, AP Science WriterWed Nov 21, 2:19 AM ET
Scientists have created the equivalent of embryonic stem cells from ordinary skin cells, a breakthrough that could someday produce new treatments for disease without the explosive moral questions of embyro cloning.
Research teams in the United States and Japan showed that a simple lab technique can rival the complex and highly controversial idea of extracting stem cells from cloned embryos.
It was a landmark achievement on all fronts, defusing one of the most divisive debates in modern medicine and religion. It was lauded by scientists, ethicists and religious groups.
"This work represents a tremendous scientific milestone — the biological equivalent of the Wright Brothers' first airplane," said Dr. Robert Lanza, whose company, Advanced Cell Technology, has been trying to extract stem cells from cloned human embryos.
"It redefines the ethical terrain," said Laurie Zoloth, a bioethicist at Northwestern University.
"It's a win-win for everyone involved," said the Rev. Thomas Berg of the Westchester Institute, a Roman Catholic think tank. "We have a way to move forward which ... brings the kind of painful national debate over this controversial research to very much a peaceful and promising resolution."
At the White House, President Bush, who vetoed two bills to allow federal funding for stem-cell research, was described as "very pleased."
"The president believes medical problems can be solved without compromising either the high aims of science or the sanctity of human life," said a statement from his press secretary.
The new technique reprograms cells, giving them the chameleon-like qualities of embryonic stem cells, which can morph into all kinds of tissue, such as heart, nerve and brain. As with embryonic cells, the hope is to speed medical research. For example, one day an ailing patient might benefit from genetically matched healthy tissue that would replace damaged cells.
The research was published online Tuesday by two journals, Cell and Science. The Cell paper is from a team led by Dr. Shinya Yamanaka of Kyoto University; the team published by Science was led by Junying Yu, working in the lab of stem-cell pioneer James Thomson of the University of Wisconsin-Madison.
Both groups reported that the reprogrammed cells behaved like stem cells in a series of lab tests. Their papers ended a scientific race that broke into wide view just this summer, when the achievement was reported in mice.
The scientists themselves were startled by their success.
"I was surprised when we achieved our results with the mouse," Yamanaka said. "But proving what we could do with human cells really bowled me over."
Thomson said he was surprised it didn't take longer to discover how to reprogram ordinary cells. The technique, he said, is so simple that "thousands of labs in the United States can do this, basically tomorrow."
In contrast, the cloning approach is so complex and expensive that many scientists say it couldn't be used routinely to supply stem cells for therapy.
While the discovery seems likely to shift the direction of research, Thomson and others said it's too soon to give up on studying embryonic stem cells.
He said he believes the ethical turmoil surrounding the embryonic cells set the field back four or five years. The new results are "probably the beginning of the end for that controversy," he said.
But he said his team wasn't trying to find a way around the ethical debate by pursuing the new technique. "We just thought this was a more practical approach," he said.
An official of one group fiercely opposed to destroying embryos saw things differently, saying scientists should thank "pro-life voices" for pushing them to find alternatives.
"The results are groundbreaking studies like these," said Carrie Gordon Earll, bioethics analyst for Focus on the Family, a conservative Christian group.
The controversy over embryonic stem cells has been a touchstone of national politics. It inspired impassioned pleas by Nancy Reagan, the actor Michael J. Fox, who suffers from Parkinson's disease, and countless ordinary citizens arguing in favor of the potential medical benefits.
Equally heartfelt were objections that destroying embryos to extract the stem cells meant destroying human life.
No federal money was available for embryonic stem cell research until 2001, when President Bush allowed very limited funding. Some states like California and Connecticut responded to his restrictions by setting up their own programs to pay for it.
The new work shows that like cloning, "direct reprogramming" can also use ordinary body cells to create versatile cells that are genetically matched.
"It's a bit like learning how to turn lead into gold," said Lanza, while cautioning that the work is far from providing medical payoffs.
"It's a huge deal," agreed Rudolf Jaenisch, a prominent stem cell scientist at the Whitehead Institute in Cambridge, Mass. "You have the proof of principle that you can do it."
There is a catch. At this point, the technique disrupts the DNA of the skin cells, and that creates the potential for developing cancer. So it would be unacceptable for transplanting into a patient.
But the DNA disruption is just a byproduct of the technique, and experts said they believe it can be avoided.
For the new work, the two scientific teams chose different cell types from a tissue supplier. Yamanaka reprogrammed skin cells from the face of an unidentified 36-year-old woman, and Thomson's team worked with foreskin cells from a newborn. Thomson's team, which was working its way from embryonic to fetal to adult cells, is still analyzing its results with adult cells.
Both labs did basically the same thing. Each used viruses to ferry four genes into the skin cells. These particular genes were known to turn other genes on and off, but just how they produced cells that mimic embryonic stem cells is a mystery.
Both Thomson, 48, and Yamanaka, 45, had already produced notable achievements. Thomson made headlines in 1998 when he announced that his team had isolated human embryonic stem cells.
And Yamanaka gained scientific notice in 2006 by reporting that direct reprogramming in mice had produced cells resembling embryonic stem cells, although with significant differences. In June, his group and two others announced they'd created mouse cells that were virtually indistinguishable from stem cells.
Zoloth, the ethicist at Northwestern, noted that direct reprogramming avoids not only embryo destruction, but also the need for unfertilized human eggs to create embryos. Eggs are hard to obtain for research, and collecting them subjects women to drug treatment and surgery. Using eggs also raises the ethical question of whether women should be paid for them.
The embryo and egg issues were "show-stopping ethical problems," she said.
Another advantage of direct reprogramming is that it would qualify for federal research funding, unlike projects that seek to extract stem cells from human embryos, noted Doug Melton, co-director of the Harvard Stem Cell Institute.
Still, scientific questions remain about the cells produced by direct reprogramming, called "iPS" cells. One is how the cells compare to embryonic stem cells in their behavior and potential. Eventually, iPS cells might prove better for some scientific uses and cloned stem cells preferable for other uses. For example, scientists want to study the roots of genetic disease and screen potential drug treatments in their laboratories.
Scottish researcher Ian Wilmut, famous for his role in cloning Dolly the sheep a decade ago, has said he is giving up the cloning approach to produce stem cells and plans to pursue direct reprogramming instead.
Other scientists said it's too early for the field to give up studying stem cells from embryos.
Dr. George Daley of the Harvard institute, who said his own lab has also achieved direct reprogramming of human cells, said it's not clear how long it will take to get around the cancer risk problem.
His lab is pursuing both the reprogramming and cloning strategies.
"We'll see, ultimately, which one works and which one is more practical," he said,
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On the Net:
Journal Cell: http://www.cell.com
Journal Science: http://www.sciencemag.org