Stem Cell Research Reveals Culprit In Aging Muscles That Heal Poorly

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Stem Cell Research Reveals Culprit In Aging Muscles That Heal Poorly

http://www.medicalnewstoday.com/articles/79373.php

Communication is critical. Garbled in, garbled out, so to (mis-)

speak. Workers who get incomplete instructions produce an incomplete

product, and that's exactly what happens with the stem cells in our

aging muscles, according to researchers from the Stanford University

School of Medicine.

Their study found that, as we age, the lines of communication to the

stem cells of our muscles deteriorate and, without the full

instructions, it takes longer for injured muscles to heal. Even

then, the repairs aren't as good. But now that the researchers have

uncovered the conduit that conveys the work orders to muscle stem

cells, that knowledge could open the door to new therapies for

injuries in a host of different tissues.

The key to the whole 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 Rando, MD, PhD, 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, who also does research and clinical work at

the Veterans Affairs Palo Alto Health Care System, is senior author

of the research that will be published in 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.

It was while the researchers were testing the opposite situation -

how the repair capabilities of young muscle stem cells were affected

by being placed in an aged environment - that the Wnt pathway came

to light. 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 -- the ones 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.

Rando said that, although the work of his team and the NIH

researchers 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. "