Old Muscle Given New Pep By Stem Cell Researchers

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Old Muscle Given New Pep By Stem Cell Researchers

http://www.medicalnewstoday.com/articles/111521.php

Old muscle got a shot of youthful vigor in a stem cell experiment by

bioengineers at the University of California, Berkeley, setting the

path for research on new treatments for age-related degenerative

conditions such as muscle atrophy or Alzheimer's and Parkinson's

diseases.

In a new study published in an advanced online issue of the journal

Nature, researchers identified two key regulatory pathways that

control how well adult stem cells repair and replace damaged tissue.

They then tweaked how those stem cells reacted to those biochemical

signals to revive the ability of muscle tissue in old mice to repair

itself nearly as well as the muscle in the mice's much younger

counterparts.

Irina Conboy, an assistant professor of bioengineering and an

investigator at the Berkeley Stem Cell Center and at the California

Institute for Quantitative Biosciences (QB3), led the research team

conducting this study.

Because the findings relate to adult stem cells that reside in

existing tissue, this approach to rejuvenating degenerating muscle

eliminates the ethical and medical complications associated with

transplanting tissues grown from embryonic stem cells.

" We are one step closer to having a point of intervention where we

can rejuvenate the body's own stem cells so we don't have to suffer

from some of the debilitating diseases associated with aging, " said

the study's lead author, Carlson, a recent Ph.D. graduate of

Conboy's lab.

The researchers focused on the interplay of two competing molecular

pathways that control the stem cells, which sit next to the mature,

differentiated cells that make up our working body parts. When the

mature cells are damaged or wear out, the stem cells are called into

action to begin the process of rebuilding.

" We don't realize it, but as we grow our bodies are constantly being

remodeled, " said Conboy. " We are constantly falling apart, but we

don't notice it much when we're young because we're always being

restored. As we age, our stem cells are prevented, through chemical

signals, from doing their jobs. "

The good news, the researchers said, is that the stem cells in old

tissue are still ready and able to perform their regenerative

function if they receive the appropriate chemical signals. Studies

have shown that when old tissue is placed in an environment of young

blood, the stem cells behave as if they are young again.

" Conversely, we have found in a study published last year that even

young stem cells rapidly age when placed among blood and tissue from

old mice, " said Carlson, who will stay on at UC Berkeley to expand

his work on stem cell engineering either as a QB3 fellow or a

postdoctoral researcher. He will be supervised by Conboy; Tom Alber,

professor of biochemistry; and Schaffer, associate director of

the Berkeley Stem Cell Center and professor of chemical engineering.

Adult stem cells have a receptor called Notch that, when activated,

tells them that it is time to grow and divide, the researchers said.

But stem cells also have a receptor for the protein TGF-beta that

sets off a chain reaction activating the molecule pSmad3 and

ultimately producing cyclin-dependent kinase (CDK) inhibitors, which

regulate the cell's ability to divide.

" Interestingly, activated Notch competes with activated pSmad3 for

binding to the regulatory regions of the same CDK inhibitors in the

stem cell, " said Conboy. " We found that Notch is capable of

physically kicking off pSmad3 from the promoters for the CDK

inhibitors within the stem cell's nucleus, which tells us that a

precise manipulation of the balance of these pathways would allow the

ability to control stem cell responses. "

Notch and TGF-beta are well known in molecular biology, but Conboy's

lab is the first to connect them to the process of aging, and the

first to show that they act in opposition to each other within the

nucleus of the adult stem cell.

Aging and the inevitable march towards death are, in part, due to the

progressive decline of Notch and the increased levels of TGF-beta ,

producing a one-two punch to the stem cell's capacity to effectively

rebuild the body, the researchers said.

" What we discovered is the interplay between two pathways - one an

aging pathway, and the other a youthful pathway, " said Conboy.

But what would happen if researchers blocked the adult stem cells in

old tissues from reacting to those TGF-beta signals? The researchers

put that question to the test in a living organism by comparing the

muscle regeneration capacity of old, 2-year-old mice, comparable in

age to a 75- to 80-year-old human, with that of 2-month-old mice,

similar in age to a 20- to 25-year-old human.

For a group of the old mice, the researchers disabled the " aging

pathway " that tells stem cells to stop dividing by using an

established method of RNA interference that reduced levels of pSmad3.

The researchers then examined the muscle of the different groups of

mice one to five days after injury to compare how well the tissue

repaired itself.

As expected, the researchers found that muscle tissue in the young

mice easily replaced damaged cells with new, healthy cells. In

contrast, the areas of damaged muscle in the control group of old

mice were characterized by fibroblasts and scar tissue.

However, muscles in the old mice whose stem cell " aging pathway " had

been dampened showed levels of cellular regeneration that were

comparable to their much younger peers, and that were 3 to 4 times

greater than those of the group of " untreated " old mice.

The researchers cautioned that shutting down the TGF-beta/pSmad3

pathway altogether by turning off the gene that controls it could

lead to many health problems. The ability to suppress cell division

is critical in controlling the development of tumors, for instance.

" When we are young, there is an optimal balance between Notch and TGF-

beta, " said Conboy. " We need to find out what the levels of these

chemicals are in the young so we can calibrate the system when we're

older. If we can do that, we could rejuvenate tissue repair for a

very long time. "

The researchers also warn against interpreting this research as the

cure-all for aging.

" We're not at a point where we're ready to inject ourselves with TGF-

beta antibodies and call it a day, " said Carlson. " There are multiple

mechanisms involved in how our body functions. We know that TGF-beta

is involved in one aspect of aging, but we don't know where it fits

in the global scheme of aging. "

In addition to their work on adult stem cells, Carlson and Conboy

have also discovered that human embryonic stem cells can actually

neutralize the effects of aging. Conboy received funding last year

from the California Institute for Regenerative Medicine (CIRM) to

pursue this line of research.