How Stem Cells Decide To Become Either Skeletal Or Smooth Muscle
ScienceDaily (Oct. 12, 2007) — Researchers have discovered a key
protein that controls how stem cells "choose" to become either
skeletal muscle cells that move limbs, or smooth muscle cells that
support blood vessels, according to a study published recently in the
Proceedings of the National Academy of Sciences (PNAS). The results
not only provide insight into the development of muscle types in the
human fetus, but also suggest new ways to treat atherosclerosis and
cancer, diseases that involve the creation of new blood vessels from
stem cell reserves that would otherwise replace worn out skeletal
muscle.
The newly discovered mechanism also suggests that some current cancer
treatments may weaken muscle, and that physician researchers should
start watching to see if a previously undetected side effect exists.
Thanks to stem cells, humans develop from a single cell into a
complex being with as many as 400 cell types in millions of
combinations. The original, single human stem cell, the fertilized
embryo, has the potential to develop into every kind of human cell.
As we develop in the womb, successive generations of stem cells
specialize (differentiate)
fewer cell types.
One set of mostly differentiated stem cells has the ability to become
bone, blood, skeletal muscle or smooth muscle. Many human tissues
keep a reserve of stem cells on hand in adulthood, ready to
differentiate into replacement parts depending on the stimuli they
receive. If body signals that skeletal muscle needs replacing, the
stem cells take that route. If tissues signal for more blood vessels,
the same stem cells may become smooth muscle that supports the lining
of blood vessels.
In the current study a team of researchers at the Aab Cardiovascular
Research Institute of the University of Rochester School of Medicine
& Dentistry and at the University of Texas Southwestern Medical
Center found that a transcription factor called myocardin may be the
master regulator of whether stem cells become skeletal or smooth
muscle. Myocardin is a transcription factor, a protein designed to
associate with a section of the DNA code, and to turn the expression
of that gene on or off. Until now, Myocardin was only thought of as a
protein that turns on genes that make smooth muscle cells. In the
PNAS report, Myocardin is shown to also turn off genes that make
skeletal muscle.
"These findings could eventually lead to stem-cell based therapies
where researchers take control of what the stem cell does once
implanted through the action of transcription factors like myocardin,
unlike current therapies that "hope" the stem cell will take a
correct differentiation path to fight disease," said Joseph M. Miano,
Ph.D., senior author of the paper and associate professor within the
Aab Cardiovascular Research Institute at the University of Rochester
Medical Center "More specifically, many diseases are driven by
whether stem cells decide to become skeletal muscle, or instead to
become part of new blood vessel formation. These discoveries have
created a new wing of medical research that seeks to understand the
genetic signals that turn on such stem cell replacement programs."
Atherosclerosis, or hardening of the arteries, for instance, becomes
likely to cause heart attack or stroke when cholesterol-
plaques that build up inside of arteries become fragile. If they
rupture, they interact with circulating factors into the blood to
cause clots that block arteries and lead to tissue death.
Theoretically, injecting stem cells programmed them to become smooth
muscle could strengthen the plaques and prevent rupture, Miano said.
Conversely, tumors must be able to grow blood vessels in order to
grow. They do so by sending signals for stem cells to form smooth
muscle in combination with other signals that turn on vascular
endothelial growth factor (VEGF), which together build new blood
vessels. Would manipulating myocardin along with VEGF interfere with
tumor growth by cutting off its blood supply? Do current VEGF-based
treatments kick myocardin into action, creating smooth muscle instead
of continually repairing worn out skeletal muscle? Since VEGF is used
experimentally to treat peripheral artery disease and coronary artery
disease, is this treatment reducing the skeletal muscle strength of
these patients?
Miano's team found that myocardin both turns on a set of genes that
turns stem cells into smooth muscle, and turns off the genes that
turn stem cells into skeletal muscle, making it a bifunctional,
developmental switch. The team at Southwestern applied the same idea
to the development of the fetus via transgenic mouse studies,
providing the biological context that made sense of Miano's finding.
Researchers at many institutions have been studying the somite, a
group of cells in the human fetus known to develop into skeletal
muscle. The team in Southwestern did cell lineage and tracking
studies and found that myocardin is expressed briefly in the somite
during development in mice, but then disappears from that region of
the fetus. This current data leads to the surprising theory that both
skeletal and smooth muscle cells come from the same stem cell region.
Myocardin briefly switches on to make the new human's supply of
smooth muscle cells, which then migrate to another area where they
begin to form blood vessels. Myocardin then quickly shuts off,
allowing the somite to continue differentiating into skeletal muscle.
If it did not, then skeletal muscle would not develop properly.
Larger Picture
Miano's team is one of many in recent years seeking to define ancient
sections of our genetic code that may soon be as important to medical
science as genes. A new wave of research is concerned with, not how
genes work, but how small regulatory DNA sequences tell genes where,
when and to what degree to "turn on" in combination with enzymes that
seek them out.
Genes are the chains of deoxyribonucleic acids (DNA) that encode
instructions for the building of proteins, the workhorses that make
up the body's organs and carry its signals. Growing knowledge of how
regulatory sequences control gene behavior has the potential to
create new classes of treatment for nerve disorders and heart
failure. Regulatory sequences are emerging as an important part of
the non-gene majority of human genetic material, once thought of
as "junk DNA." A new frontier in genetic research is the defining of
the regulome, the complete set of DNA sequences that regulate the
precise turning on and off of genes.
In an article by Miano and team published February 2006 in the
journal Genome Research, they described one such regulatory sequence:
the CArG box. The nucleotide building blocks of DNA chains may
contain any one of four nucleobases: adenine (A), thymine (T),
guanine (G) and cytosine (C). Any sequence of code starting with 2
Cs, followed by any combination of 6 As or Ts, and ending in 2 Gs is
a CArG box.
According to Miano, there are 1,216 variations of CArG box that
together occur approximately three million times throughout the human
DNA blueprint. CArG boxes exert their influence over genes because
they are "shaped" to partner with a nuclear protein called serum
response factor (SRF) and several other proteins within a genetic
regulatory network, including Myocardin. As many as sixty genes so
far have been found to be influenced by the CArG-SRF, including many
involved in heart cell and blood vessel function.
Past studies had determined that myocardin is a cofactor with SRF in
CArG-Box mediated genetic regulation of stem cells. Up until now,
researchers believed myocardin partnered with SRF to turn on smooth
muscle genes through CArG box interaction. The current findings
suggest, however, that myocardin has a second role, independent of
its partnership with CARG-SRF, where it serves as a potent silencer
of gene expression for the stem cell to skeletal muscle gene program.
"With its dual action, myocardin is an early example of the
efficiency and elegance of the system of genetic controls, where one
factor has more than one complementary effect on the development of
the body," said Eric Olson, Ph.D., chair of the Department of
Molecular Biology at the University of Texas Southwestern Medical
Center in Dallas, and also senior author of the study.
Adapted from materials provided by University of Rochester Medical
Center.
http://www.scienced
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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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