Abstract
Interactions between stem cells and their microenvironment, or niche, are essential for stem cell maintenance and function. Our knowledge of the niche for the skeletal muscle stem cell, i.e., the satellite cell (SC), is incomplete. Here we show that β1-integrin is an essential niche molecule that maintains SC homeostasis, and sustains the expansion and self-renewal of this stem cell pool during regeneration. We further show that β1-integrin cooperates with fibroblast growth factor 2 (Fgf2), a potent growth factor for SCs, to synergistically activate their common downstream effectors, the mitogen-activated protein (MAP) kinase Erk and protein kinase B (Akt). Notably, SCs in aged mice show altered β1-integrin activity and insensitivity to Fgf2. Augmenting β1-integrin activity with a monoclonal antibody restores Fgf2 sensitivity and improves regeneration after experimentally induced muscle injury. The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice, a model for Duchenne muscular dystrophy. Therefore, β1-integrin senses the SC niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.
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Acknowledgements
We thank E. Dikovskaia and S. Satchell for technical assistance, and C. Lepper, Y. Zheng and members of the Fan laboratory for comments. We especially thank A. Wagers for generously sharing the FACS and SC isolation protocol. Funding for this work was provided by the Carnegie Institution (C.-M.F.) and the National Institutes of Health (NIH) (grant no. AR060042; C.-M.F.). M.R. is supported by a predoctoral fellowship from the NIH (HD075345), and L.L. is supported by Carnegie Institution of Washington internal funds.
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M.R. and C.-M.F. conceptualized the study; M.R. performed experimental analysis for the mutant mice, as well as for the FACS and RNA-seq data, and demonstrated the utility of TS2/16; L.L. performed mechanistic experiments to investigate integrin–FGF synergy and conducted in situ muscle force measurements. C.-M.F. initiated and supervised the project. All three authors wrote, discussed and edited the manuscript.
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Rozo, M., Li, L. & Fan, CM. Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice. Nat Med 22, 889–896 (2016). https://doi.org/10.1038/nm.4116
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DOI: https://doi.org/10.1038/nm.4116
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