期刊
CELL STEM CELL
卷 24, 期 3, 页码 419-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2019.01.002
关键词
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资金
- QEII-GSST
- CIHR
- OIRM
- AFM-Telethon
- Canada Research Chair in Molecular Genetics
- NIH [R01AR044031]
- Canadian Institutes for Health Research [FDN-148387]
- E-Rare-2: Canadian Institutes of Health Research/Muscular Dystrophy Canada [ERA-132935]
- Muscular Dystrophy Association
- Ontario Institute for Regenerative Medicine
- Stem Cell Network
Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.
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