Abstract
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. OSM is produced by muscle fibers, induces reversible MuSC cell cycle exit, and maintains stem cell regenerative capacity as judged by serial transplantation. Conditional OSM receptor deletion in satellite cells leads to stem cell depletion and impaired regeneration following injury. These results identify Oncostatin M as a secreted niche factor responsible for quiescence induction, and for the first time establish a direct connection between induction of quiescence, stemness, and transplantation potential in solid organ stem cells.
Highlights
The balance between stem cell quiescence and proliferation in skeletal muscle is tightly controlled, but perturbed in a variety of disease states
We hypothesized that a secreted regulator of stem cell quiescence would be capable of suppressing muscle stem cells (MuSC) activation and proliferation in vitro, while maintaining the ability of these cells to engraft following transplantation in vivo
The ability of Oncostatin M (OSM) to promote MuSC engraftment without inducing proliferation is distinct from previously reported factors such as regulators of p38 MAPK6,10, as well as related cytokines such as IL-6 and Leukemia Inhibitory Factor (LIF) (Fig. 2h)[18,20,21,37]
Summary
The balance between stem cell quiescence and proliferation in skeletal muscle is tightly controlled, but perturbed in a variety of disease states. A subset of activated satellite cells are re-selected into the quiescent stem cell niche in order to maintain the stem cell pool[1] This process is highly regulated, involving cell autonomous signaling pathways, and extensive regulation by tissue resident stromal cells and invading inflammatory cell populations[2]. Interpretation of the results of genetic and pharmacologic STAT3 inhibition is complicated, by the fact that this effector can be activated by numerous upstream signals, including both IL-6 and other cytokines[22] Despite this progress, the precise signals governing the choice between quiescence and proliferation remain poorly understood, and this constitutes a major barrier to reversing the regenerative block seen in a variety of disease states. Employing an unbiased in vitro/in vivo imaging based screening strategy, we identify Oncostatin M, a member of the IL-6 family of cytokines, as a novel regulator of stem cell quiescence, engraftment, and muscle regeneration
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