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Cell Stem Cell. 2019 Mar 7;24(3):419-432.e6. doi: 10.1016/j.stem.2019.01.002. Epub 2019 Jan 31.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Author information

1
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
2
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
3
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: mrudnicki@ohri.ca.

Abstract

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.

KEYWORDS:

Aurka; Duchenne muscular dystrophy; EGF; EGFR; apicobasal polarity; asymmetric cell division; muscle stem cell; satellite cell; skeletal muscle

PMID:
30713094
PMCID:
PMC6408300
[Available on 2020-03-07]
DOI:
10.1016/j.stem.2019.01.002

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