Skeletal muscle has a remarkable capacity to regenerate following exercise or injury and harbors two different types of adult stem cells to accomplish the job: satellite cells and adult stem cells that can be isolated as side population (SP) cells. A certain group of these stem cells is involved in muscle tissue repair, but is only triggered into the muscle cell development pathway by injury. The question then arises: what molecular factors turn these adult stem cells into muscle cells? Now Michael Rudnicki and colleagues have shown that one gene, Pax7, has a crucial role in this process.
In previous studies, Rudnicki's group demonstrated that Pax7 is required to turn adult stem cells into muscle cells during regeneration. Here, the researchers worked with mouse models and in vitro experiments to investigate whether Pax7 is sufficient to initiate muscle cell formation in injured tissue.
They show that stem cells taken from regenerating muscle in mice lacking the Pax7 gene could not become muscle cells, and that by putting Pax7 back into stem cells taken from uninjured muscle, they can generate a population of cells that readily differentiate into muscle cells. When stem cells engineered to express Pax7 proteins were injected into the muscles of mice lacking dystrophin (the protein defective in muscular dystrophy), the cells differentiated, forming dystrophin-expressing muscle cells in the defective muscle. This shows that engineered "donor cells" can differentiate in living tissue and help repair damaged muscle of recipient mice. When the researchers injected Pax7 (using a gene therapy virus) into the damaged muscle of mice lacking Pax7, they observed the production of muscle-forming cells that not only gave rise to differentiated muscle cells, but also aided in tissue repair.
The researchers argue that these results "unequivocally establish" Pax7 as a key regulator of muscle cell differentiation in specific populations of adult stem cells during muscle tissue regeneration in mice. If therapeutic strategies that activate Pax7 in adult stem cells can turn them into muscle cells, effectively replenishing injured or diseased muscle tissue, there's hope of reversing the debilitating effects of progressive muscle-wasting diseases. Though the usefulness of such an approach in humans will require intensive investigation, the results on these mouse adult stem cells are encouraging.
citation: Seale P, Ishibashi J, Scim A, Rudnicki MA (2004) Pax7 is necessary and sufficient for the myogenic specification of CD45+:Sca1+ stem cells from injured muscle. PLoS Biol 2(5): e130 DOI:10.1371/journal.pbio.0020130
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