Cellular and molecular regulation of muscle stem cells

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DESCRIPTION (provided by applicant): Muscle precursor cells (MFC) are tissue specific stem cells critical for muscle growth and regeneration. MPC are normally quiescent but in response to a growth stimulus are activated to proliferate and undergo differentiation/fusion. A portion of MPC must remain undifferentiated such that the MPC pool is restored and available to meet future growth requirements. The mechanisms that regulate MPC self-renewal vs. differentiation have been little studied. Stem cell antigen-1 (Sca-1, Ly-6A/E) is a member of the Ly-6 family of proteins that have been extensively studied in immune cells. The function of Sca-1 is largely unknown, but functions as diverse as cell signaling, cell adhesion and regulation of stem cell self-renewal have been proposed in immune cells. Based on our preliminary data, we postulate that Sca-1 plays a role in regulating the MPC pool during periods of growth. We show that Sca-lpos cells represent a pool of MPC that replicate slower and do not differentiate. We hypothesize that Sca-1 expression serves as a protective mechanism to maintain an adequate pool of MPC in muscle tissue after MPC activation. A set of 4 aims are proposed to analyze Sca-1 function in vitro (Aim 1) and in vivo (Aim 2) , regulation of its expression by cytokines and NFAT dependent signaling (Aim 3) and cloning of its ligand (Aim 4). A combination of cellular and molecular approaches will be utilized. Our proposed studies will define a novel pathway in muscle for regulating tissue specific stem cells. Studies of Sca-1 may lead to new strategies for manipulating myogenic stem cells in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.