Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration

摘要

Even in adulthood, injured muscles can repair themselves largely because they contain groups of stem cells known as satellite cells. These cells divide to produce progenitor cells that later develop, or differentiate, into new muscle fibers. However as muscles get older, this repair process becomes less effective, in part because the satellite cells do not respond as strongly to injury. It remains obscure precisely why the repair process declines with age. A protein called TGFβ is part of a signaling pathway that prevents the muscle progenitor cells from differentiating into muscle fibers, and TGFβ signaling is overactive in older muscles. Most TGFβ signaling operates via a protein called Smad4, and Paris et al. now show that older satellite cells and progenitor cells from the muscles of old mice produce less Smad4 when they are regenerating. Next, the gene for Smad4 was deleted specifically from the satellite cells of mice. By examining the fate of these cells, Paris et al. found that Smad4 normally maintained the population of satellite cells by preventing them from differentiating into muscle fibers too soon. This was the case when both adult and aged muscle was regenerating. All in all, Smad4 is clearly important for directing satellite cells to regenerate properly; aged cells have less Smad4 and are less able to regenerate. Future studies are now needed to determine how disrupting Smad4 in other resident cell types may influence the regeneration of muscles in mice.