Molecular regulation of muscle stem cell asymmetric division

Description

Abstract We discovered that a subset of satellite cells in skeletal muscle are self-renewing stem cells that give rise to myogenic progenitors through asymmetric apical-basal cell divisions. The regulation of asymmetric stem cell division is a key control point that impacts the efficacy of the entire regenerative program. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. Duchenne Muscular Dystrophy (DMD) is coaused by a lack of dystrophin which is expressed in muscle fibers where it plays a role in ensuring structural integrity. We have made the seminal finding that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggests that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather is due to a cell-autonomous deficiency in asymmetric division.

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