Study Reveals how Stem Cells Decide to Become either Skeletal or Smooth Muscle
News Oct 11, 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 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.
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-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.
The question of how primitive, undifferentiated cells choose their destiny has tantalized biologists for centuries. New clues about the molecular logic of cell fate show that multipotent cells become biased towards a fate early on and step through a progression of binary decisions as their fate is refined.READ MORE