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Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M

ABSTRACT: Regeneration of skeletal muscle is dependent on the function of tissue-resident muscle stem cells (MuSC), known as satellite cells. MuSC dysfunction is central to muscle pathophysiology, including in age-associated loss of muscle regenerative capacity and congenital disorders such as Duchenne muscular dystrophy. Despite the central role of satellite cells in muscle regeneration, the signals controlling the balance between muscle stem cell quiescence, proliferation, and differentiation remain incompletely understood. Knowledge of the signals that maintain a quiescent state is particularly lacking, yet such cues are crucial to maintaining a stem cell reservoir that can meet the needs of regeneration throughout life. Here we identify Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent and essential trans-acting regulator of satellite cell quiescence. Key to this discovery is the development of a novel in vivo imaging-based screening strategy allowing identification of proteins that do not induce in vitro proliferation, but instead maintain MuSCs in a non-mitotic state, poised for rapid robust expansion upon transplantation. We demonstrate that OSM induces reversible exit from the cell cycle and induction of a global transcriptional program significantly enriched within a newly established satellite cell “quiescence signature”. Genetic ablation of the OSM receptor in mice demonstrates that signaling via OSM/R is essential for maintenance of satellite cell quiescence, and for proper skeletal muscle regeneration in vivo. Given that aberrant activation and exhaustion of stem cells is seen in a variety of disorders, OSM constitutes an attractive therapeutic target in muscle disease states. Microarray profiling was used to directly test the hypothesis that OSMR signaling in muscle stem cells promotes their engraftment by inducing a global transcriptional state equivalent to that of quiescent, freshly isolated, non-activated MuSC. Overall design: Comparison of Oncostatin M-treated cultured muscle stem cells with either fresh or cultured but non-Oncostatin M-treated muscle stem cells

INSTRUMENT(S): [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array

SUBMITTER: John R Walker  

PROVIDER: GSE69976 | GEO | 2018-12-01


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Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M.

Sampath Srinath C SC   Sampath Srihari C SC   Ho Andrew T V ATV   Corbel Stéphane Y SY   Millstone Joshua D JD   Lamb John J   Walker John J   Kinzel Bernd B   Schmedt Christian C   Blau Helen M HM  

Nature communications 20180418 1

The balance between stem cell quiescence and proliferation in skeletal muscle is tightly controlled, but perturbed in a variety of disease states. Despite progress in identifying activators of stem cell proliferation, the niche factor(s) responsible for quiescence induction remain unclear. Here we report an in vivo imaging-based screen which identifies Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent inducer of muscle stem cell (MuSC, satellite cell) quiescence.  ...[more]

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