Stem cell transplants in mice produce lifelong enhancement of muscle mass

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http://eurekalert.org/pub_releases/2010-11/uoca-sct110810.php

Contact: Bradley Olwin

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University of Colorado at Boulder

Stem cell transplants in mice produce lifelong enhancement of muscle mass

Findings may have potential for future treatment of patients with chronic,

degenerative muscle diseases

A University of Colorado at Boulder-led study shows that specific types of stem

cells transplanted into the leg muscles of mice prevented the loss of muscle

function and mass that normally occurs with aging, a finding with potential uses

in treating humans with chronic, degenerative muscle diseases.

The experiments showed that when young host mice with limb muscle injuries were

injected with muscle stem cells from young donor mice, the cells not only

repaired the injury within days, they caused the treated muscle to double in

mass and sustain itself through the lifetime of the transplanted mice. " This was

a very exciting and unexpected result, " said Professor Bradley Olwin of

CU-Boulder's molecular, cellular and developmental biology department, the

study's corresponding author.

Muscle stem cells are found within populations of " satellite " cells located

between muscle fibers and surrounding connective tissue and are responsible for

the repair and maintenance of skeletal muscles, said Olwin. The researchers

transplanted between 10 and 50 stem cells along with attached myofibers -- which

are individual skeletal muscle cells -- from the donor mice into the host mice.

" We found that the transplanted stem cells are permanently altered and reduce

the aging of the transplanted muscle, maintaining strength and mass, " said

Olwin.

A paper on the subject was published in the Nov. 10 issue of Science

Translational Medicine. Co-authors on the study included former CU-Boulder

postdoctoral fellow K. Hall, now at the University of Washington Medical

School in Seattle, as well as Glen Banks and Chamberlain of the

University of Washington Medical School.

Olwin said the new findings, while intriguing, are only the first in discovering

how such research might someday be applicable to human health. " With further

research we may one day be able to greatly resist the loss of muscle mass, size

and strength in humans that accompanies aging, as well as chronic degenerative

diseases like muscular dystrophy. "

Stem cells are distinguished by their ability to renew themselves through cell

division and differentiate into specialized cell types. In healthy skeletal

muscle tissue, the population of satellite stem cells is constantly maintained,

said Olwin.

" In this study, the hallmarks we see with the aging of muscles just weren't

occurring, " said Olwin. " The transplanted material seemed to kick the stem cells

to a high gear for self-renewal, essentially taking over the production of

muscle cells. But the team found that when transplanted stem cells and

associated myofibers were injected to healthy mouse limb muscles, there was no

discernable evidence for muscle mass growth.

" The environment that the stem cells are injected into is very important,

because when it tells the cells there is an injury, they respond in a unique

way, " he said. " We don't yet know why the cells we transplanted are not

responding to the environment around them in the way that the cells that are

already there respond. It's fascinating, and something we need to understand. "

At the onset of the experiments the research team thought the increase in muscle

mass of the transplanted mice with injured legs would dissipate within a few

months. Instead, the cells underwent a 50 percent increase in mass and a 170

percent increase in size and remained elevated through the lifetime of the mice

-- roughly two years, said Olwin.

In the experiments, stem cells and myofibers were removed from three-month-old

mice, briefly cultured and then transplanted into three-month-old mice that had

temporarily induced leg muscle injuries produced by barium chloride injections.

" When the muscles were examined two years later, we found the procedure

permanently changed the transplanted cells, making them resistant to the aging

process in the muscle, " he said.

" This suggests a tremendous expansion of those stem cells after

transplantation, " Olwin said. Fortunately, the research team saw no increase in

tumors in the transplanted mice despite the rapid, increased growth and

production of muscle stem cells.

As part of the research effort, the team used green fluorescent protein -- which

glows under ultraviolet light -- to flag donor cells in the injected mice. The

experiment indicated many of the transplanted cells were repeatedly fused to

myofibers, and that there was a large increase in the number of satellite cells

in the host mice.

" We expected the cells to go in, repopulate and repair damaged muscle and to

dissipate, " Olwin said. " It was quite surprising when they did not.

" It is our hope that we can someday identify small molecules or combinations of

small molecules that could be applied to endogenous muscle stem cells of humans

to mimic the behavior of transplanted cells, " Olwin said. " This would remove the

need for cell transplants altogether, reducing the risk and complexity of

treatments. "

But Olwin said it is important to remember that the team did not transplant

young cells into old muscles, but rather transplanted young cells into young

muscles.

The research has implications for a number of human diseases, Olwin said. In

muscular dystrophy, for example, there is a loss of a protein called dystrophin

that causes the muscle to literally tear itself apart and cannot be repaired

without cell-based intervention. Although injected cells will repair the muscle

fibers, maintaining the muscle fibers requires additional cell injections, he

said.

" Progressive muscle loss occurs in a number of neuromuscular diseases and in

muscular dystrophies, " he said. " Augmenting a patient's muscle regenerative

process could have a significant impact on aging and diseases, improving the

quality of life and possibly improving mobility. "

Olwin said the research team is beginning experiments to see if transplanting

muscle stem cells from humans or large animals into mice will have the same

effects as those observed in the recent mouse experiments. " If those experiments

produce positive results, it would suggest that transplanting human muscle stem

cells is feasible, " he said.

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The research was funded in part by the National Institutes of Health and the

Muscular Dystrophy Association.