MDA RESEARCHERS DISCOVER POSSIBLE KEY
TO EFFECTIVE STEM CELL THERAPY IN MUSCLE DISEASES
TUCSON, Ariz., Sept. 15, 2000 - Researchers funded by the Muscular Dystrophy Association have discovered a molecular switch in stem cells that might lead to effective stem cell therapy for muscular dystrophies - a genetically diverse group of diseases that cause disabling muscle weakness and wasting in hundreds of thousands of Americans.
The switch - identified by MDA grantee Michael Rudnicki at Canada's Ottawa Hospital Research Institute - appears to be needed for stem cells to produce satellite cells. Satellite cells exist in adult skeletal muscle and efficiently add to muscle mass during growth, after exercise and in response to muscle injury.
"Stem cells hold the potential to repair muscle damaged by several forms of muscular dystrophy," MDA Director of Science Technology Donald S. Wood said. "This study is an exciting step forward because we now have an important clue to help explain what might trigger a stem cell to home in on damaged muscle."
Stem cells - self-renewing cells that generate all of the cells in the body - can promote tissue regeneration. Many stem cells are pluripotent, meaning they have the potential to give rise to several different cell types, including those that make up bone, blood, fat, nerve and muscle.
The switch identified by Rudnicki, described in today's cover article of the journal Cell, might be used to force stem cells in adult muscle to produce satellite cells.
In a person with muscular dystrophy, "We could then have these [satellite] cells, which are committed to become muscle, repopulate damaged muscles throughout the body," Rudnicki said, emphasizing that this approach is speculative at present.
Satellite cells, Rudnicki explained, might be ideal for cell replacement therapy in muscular dystrophies and other disorders that cause wasting of muscle tissue, because they normally contribute to muscle repair by producing myogenic precursor cells (cells that form new muscle). Satellite cells also sustain their own numbers by reproducing themselves.
Previous attempts at replacing lost muscle fibers in humans and animals have had limited success, he suggested, because researchers tried using either pluripotent stem cells, which aren't very efficient at finding their way to muscle, or myogenic precursor cells, which partially repair muscle but mostly die off. Satellite cells lie somewhere in between these two cell types, destined either to renew themselves or to repair muscle.
The switch that seems to tell stem cells to produce satellite cells is a transcription factor (a protein that can turn genes on or off) called Pax7, which was previously shown to play a role in embryonic development. Patrick Seale, a graduate student in Rudnicki's laboratory, made the discovery that Pax7 persists in adult muscle, and is enriched in satellite cells.
Rudnicki and Seale examined adult mice that had the Pax7 gene deleted, and found that the mice had small muscles devoid of satellite cells. They were able to isolate stem cells from the Pax7-deficient muscles, but unlike stem cells from normal muscle (which divided to make mostly satellite cells and myogenic precursor cells), the stem cells lacking Pax7 made mostly blood cells.
Rudnicki, senior scientist and head of the Program in Molecular Genetics at the Ottawa Hospital Research Institute, believes that Pax7 acts as a switch that directs muscle stem cells to become satellite cells instead of blood cells. If Pax7 turns out to be sufficient for making this choice, it might be used to drive the production of satellite cells.
"If we can express Pax7 within [stem] cells, we can then tell [stem] cells that they should become satellite cells," Rudnicki said.
The finding could also have implications in gene therapy. In someone who has a genetic defect that causes muscular dystrophy, stem cells could be collected from his muscles and genetically manipulated to express Pax7 plus the appropriate corrective gene. Theoretically, those stem cells would be encouraged to produce satellite cells, which could then target damaged muscles for repair.
MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual, private contributors.
For information about MDA or referrals to MDA clinics, call (800) 572-1717, or visit MDA's Web site at www.mda.org.
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