Stem cell researchers give old muscle new pep
Berkeley - 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 to be published June 15 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, Morgan 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.
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Shown here is muscle tissue from an old mouse. After UC Berkeley
researchers manipulated the biochemical response of adult stem cells
in the old tissue, the muscle was able to...
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"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 David 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.
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As muscle tissue ages, it loses its ability to adequately repair
itself from damage. Instead of creating healthy, new cells to replace
damaged ones, the old muscle tissue is left...
Click here for more information.
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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.
###
Michael Hsu, a former UC Berkeley postdoctoral researcher in
bioengineering, also co-authored this paper.
This study was primarily supported by the National Institutes of
Health and The Ellison Medical Foundation, with additional funds from
a pre-doctoral training grant from CIRM.
Public release date: 15-Jun-2008
Contact: Sarah Yang
scyang@berkeley.
510-643-7741
University of California - Berkeley
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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