Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice.

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 FGF-2, a potent growth factor for SCs, to synergistically activate their common downstream effectors Erk and Akt. Importantly, SCs in aged mice display altered β1-integrin activity and insensitivity to FGF-2. Augmenting β1-integrin activity with a monoclonal antibody restores FGF-2 sensitivity and improves regeneration after experimentally-induced muscle injury. The same treatment also enhances regeneration and function of dystrophic muscles in mdx mice. Therefore, β1-integrin senses the SC niche to maintain responsiveness to FGF-2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.