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Stem Cells Seek Out and Replace Injured Muscle
By Nancy Touchette

Two new types of stem cells have been found that can seek out injured muscle tissue and replace the damaged cells. Researchers in Italy used stem cells from blood vessels to repair muscle in mice with muscular dystrophy. And Canadian scientists found that stem cells from damaged muscle give rise to new muscle fibers.

The studies reveal how different types of stem cells repair injured muscle and point to a common theme: Damaged tissues send out molecular signals that attract stem cells. The stem cells then multiply and form new muscle fibers, replacing the injured tissue.

One leg a of dystrophic mouse injected with stem cells (top) develops new muscle cells (green) while the untreated leg (bottom) does not.

This theme recurs in other tissues as well. For example, bone marrow stem cells can home in on and repair damaged heart and pancreas tissue.

Until now the signals that recruit stem cells to sites of injury have been unknown. Understanding these signals may be key to finding new ways to replace damaged tissues by encouraging the growth of stem cells already in the body.

The research could lead to new treatments for muscle-wasting diseases, such as muscular dystrophy, and for restoring muscle strength in elderly people. Athletes may also be interested in the new findings, which lend credence to the “no pain, no gain” approach to strength training and may lead to new strategies for bulking up.

In one study, Giulio Cossu, of the Stem Cell Research Institute in Milan, Italy, and his colleagues restored muscle function to mice with muscular dystrophy. The researchers injected stem cells from the blood vessels of healthy mice into leg arteries of mice with muscular dystrophy. The stem cells, which they call “mesoangioblasts,” accumulated in the diseased muscle within hours and eventually gave rise to healthy muscle tissue.

The stem cells only cross the lining of the blood vessel and enter muscle tissue if inflammation, which occurs in muscular dystrophy, is present. Researchers have found that a protein released by damaged cells can attract mesoangioblast stem cells.

“Dystrophic muscle is damaged and releases many signals involved in inflammation,” says Cossu. “Mesoangioblasts do not promote muscle regeneration on their own.”

The dystrophic mice lack a gene called a-sarcoglycan. The same gene is defective in people with a form of muscular dystrophy known as limb-girdle muscular dystrophy. The researchers isolated stem cells from mice lacking the gene and used gene therapy to replace it. When these cells were injected into dystrophic mice, muscle was also restored.

Cossu cautions that although the results, published in Science, are promising, researchers are far from a cure. Many hurdles must be overcome before the approach can be used in humans.

For example, scaling up the procedure to repair the large muscles found in humans may require large numbers of cells, and so far, the researchers have not been able to grow human mesoangioblast stem cells in culture.

“It’s one thing to fix a muscle that is smaller than your fingernail,” says Cossu. “It’s quite another thing to fix something like a human leg muscle. That would require huge numbers of cells.”

In the second study, published in Cell, researchers in Canada found that proteins important in the development of the embryo stimulate adult muscle stem cells and guide them to sites of injury.

Michael Rudnicki and his colleagues at the Ottawa Health Research Institute in Ottawa identified stem cells from adult muscle tissue in mice, based on certain proteins found on the cell surface.

Stem cells from normal tissue would not multiply in culture, but those isolated from injured muscle readily proliferated and gave rise to new muscle cells.

“Muscle has a remarkable ability to regenerate,” says Rudnicki. “We show that this ability is due to a novel class of stem cells.”

The researchers also found that a protein released from injured muscle, called Wnt, stimulates the stem cells to form new muscle cells. Wnt also signals new muscle tissue to form in the developing embryo.

“The way adult stem cells respond to Wnt is completely analogous to what is happening in the embryo,” says Rudnicki.

Stem cells from damaged mouse muscle (red) give rise to muscle fibers (green).

As people age, these signals diminish and cells lose their ability to regenerate. But understanding the signals that trigger muscle regeneration could lead to new strategies for increasing muscle strength in both aging and diseased tissues.

“Now we have a foot in the door in trying to figure out how to manipulate these cells,” says Rudnicki. “And this same signal is likely to be operating in other types of tissue as well.”

For example, Wnt has been shown recently to stimulate the growth of adult bone marrow stem cells.

Rudnicki acknowledges that Wnt may play a role in increasing muscle mass during strength training in humans. Lifting weights causes minor injury, which leads to muscle buildup. Wnt proteins are released by injured muscle in mice, but it is not clear whether exposure to the protein is enough to trigger muscle buildup in humans.

No body builders have yet contacted Rudnicki for Wnt supplements. However, he has started a company called StemPath to develop drugs that stimulate muscle stem cells within the body. Ultimately, he hopes to develop new therapies to combat aging and treat muscular degenerative disease.

—Related Articles—

Stem cells reverse diabetes in mice

Bone marrow heals the heart

Stem cell therapies: Time to step back or forge ahead?

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Polesskaya, A. et al. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 113, 841-852 (June 27, 2003).
Snider, L., and S.J. Tapscott. Emerging parallels in the generation of skeletal muscle. Cell 113, 811-816 (June 27, 2003).
Sampaolesi, M. et al. Cell therapy of a-sarcoglycan null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science Express, July 10, 2003.

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