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Polycomb Ezh1 maintains muscle stem cells quiescence through non-canonical regulation of the Notch signaling

ABSTRACT: Organismal homeostasis and regeneration are predicated on committed stem cells which, in tissues and organs with low turnover, reside for long periods in a reversible cell cycle arrest, defined as quiescence. Inability to exit or premature escape from quiescence, as occurring in pathological conditions and aging, is detrimental as it results in either lack of stem cell mobilization or pool depletion with consequent defective tissue homeostatis and regeneration. It is therefore unsurprising that quiescence is safeguarded by multilayered regulatory mechanisms. Here, we report that Polycomb Ezh1 confers quiescence to muscle stem cells (MuSCs) through a non-canonical function. In the absence of Ezh1, MuSCs spontaneously exit quiescence and, following repeated injuries, the stem cell pool is depleted resulting in failure to sustain appropriate muscle regeneration. Rather than regulating repressive Polycomb-dependent histone H3K27 methylation, Ezh1 actively maintains the Notch signaling pathway in MuSCs. Accordingly, selective genetic reconstitution of the Notch signaling corrects stem cell number and re-establishes quiescence of Ezh1-/- MuSCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE219232 | GEO | 2023/04/04

REPOSITORIES: GEO

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Project description: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.

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Polycomb Ezh1 maintains muscle stem cells quiescence through non-canonical regulation of the Notch signaling

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