How Stem Cells Decide To Become Either Skeletal Or Smooth Muscle Revealed By Stu

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How Stem Cells Decide To Become Either Skeletal Or Smooth Muscle

Revealed By Study

http://www.medicalnewstoday.com/articles/85286.php

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 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), with each group able to become fewer and

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 ph

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-driven

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 ©. 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 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.