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Signaling Pathway Found To Be Culprit In Aging Muscles That Heal Poorly
Friday, August 10, 2007 - Stem Cell Research News
Copy of RandoThomas.jpg
 Thomas Rando
 

The lines of communication to the stem cells of aging muscles deteriorate, extending the time it takes to heal injured muscles and impairing the quality of the healing, Stanford University researchers have found.

But the researchers also uncovered the channel that conveys the work orders to muscle stem cells, a finding that could open the door to new therapies for injuries in many different tissues.

According to the scientists, the key to the process is Wnt, a protein traditionally thought to help promote maintenance and proliferation of stem cells in many tissues.

But in this instance, Wnt appears to block proper communication.

“That was a total surprise,” said Thomas Rando, M.D., Ph.D., associate professor of neurology and neurological sciences. “We had no idea that the Wnt signaling pathway would have a negative effect on stem cell function.”

Rando is senior author of the research published in the August 10 issue of Science.

Rando said many drugs can block Wnt signaling.

“Theoretically, given the number of ways to block Wnt and Wnt signaling, one could envision this becoming a therapeutic,” he said. “You could potentially enhance the healing of aged tissues by reducing this effect of Wnt signaling on the resident stem cells.”

In addition to helping the elderly heal faster and better from muscle injuries, Rando said, the potential benefits could include tissues such as skin, gut and bone marrow, or for that matter, potentially any tissue, such as liver and brain, in which stem cells contribute to normal cellular turnover.

Rando and his colleagues made the discovery while studying the effect of environment on muscle stem cell activity in mice.

Rando had already discovered that old muscle stem cells, if placed in a youthful environment, had just as great a capacity for repairing acutely damaged tissue as do young cells.

The Wnt pathway came to light while the researchers were working from the reverse angle, testing how the repair capabilities of young muscle stem cells were affected in an aged environment.

The work was done with live mice whose circulatory systems were joined, and in lab dishes with young cells immersed in serum from old blood.

As expected, the young muscle stem cells were influenced negatively by the aged environment, repairing damaged muscle tissue just as slowly and poorly as old stem cells in the same surroundings.

This confirmed their earlier research showing that the ability of muscle stem cells to regenerate tissue depends on the age of the cells’ environment (including the age of the blood supplying the tissue), not the age of the stem cell.

Although Rando’s research focused on the repair of acute trauma to muscles, he suspects that the same sort of problem arises on a lesser scale in repairing damage that results from the normal wear and tear of aging.

Rando also found that the misdirected stem cells that failed to generate new muscle cells in the old environment were instead differentiating into scar-tissue-producing cells called fibroblasts.

The stem cells weren’t just failing to respond to the garbled instructions, they were actually giving rise to daughter cells that turned into the wrong thing.

The consequence of muscle stem cells producing fewer muscle cells (myoblasts) and more fibroblasts is that the healing muscle had more scar tissue, also known as fibrosis.

“That says something about how cells decide who they’re going to be. Even if they start off knowing they’re supposed to be a muscle cell, they can change,” said Rando. “If you’re exposed to the wrong environment, it will change your fate.”

Rando said the type of fibrosis that occurs in the aging muscle tissue is the same type seen in muscular dystrophy.

He is already exploring how inhibiting Wnt signaling might help provide therapy for that disease.

Wnt has also popped up unexpectedly in work by researchers at the National Institutes of Health, published in the same issue of Science, who were studying the effects of a deficiency of a hormone called klotho.

Klotho deficiency causes a syndrome that resembles extremely rapid aging in mice, which end up dying very young compared with normal mice.

In seeking to understand why that happens, the NIH researchers discovered that klotho inhibits Wnt activity.

The hypothesis is that klotho production declines with age, and thus its effectiveness against Wnt decreases, allowing Wnt activity to pick up and disrupt the normal signaling to the stem cells in a variety of tissues studied.

Although Rando’s work is different in terms of the techniques used and the questions being studied, “what’s surprising is how supportive of each other the fundamental conclusions (of the two papers) are about Wnt signaling and aging,” he said.

Rando’s Stanford co-authors are Andrew Brack, Ph.D., postdoctoral scholar; Michael Conboy, Ph.D., postdoctoral scholar; Sudeep Roy, research assistant; Mark Lee, M.D., Ph.D., postdoctoral scholar; and Calvin Kuo, M.D., Ph.D., assistant professor of hematology.

The research was funded by the NIH, the U.S. Department of Veterans Affairs, the Ellison Medical Foundation and an NIH Director’s Pioneer Award to Rando.

Contact: Thomas Rando, 650-858-3976, rando@stanford.edu


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