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.
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| Hall, Monica N; Griffin, Christine A; Simionescu, Adriana et al. (2011) Distinct roles for classical nuclear import receptors in the growth of multinucleated muscle cells. Dev Biol 357:248-58 |
| Long, Kimberly K; Pavlath, Grace K; Montano, Monty (2011) Sca-1 influences the innate immune response during skeletal muscle regeneration. Am J Physiol Cell Physiol 300:C287-94 |
| Simionescu, Adriana; Pavlath, Grace K (2011) Molecular mechanisms of myoblast fusion across species. Adv Exp Med Biol 713:113-35 |
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| Long, Kimberly K; Montano, Monty; Pavlath, Grace K (2011) Sca-1 is negatively regulated by TGF-beta1 in myogenic cells. FASEB J 25:1156-65 |
| Pavlath, Grace K (2010) A new function for odorant receptors: MOR23 is necessary for normal tissue repair in skeletal muscle. Cell Adh Migr 4:502-6 |
| Griffin, Christine A; Apponi, Luciano H; Long, Kimberly K et al. (2010) Chemokine expression and control of muscle cell migration during myogenesis. J Cell Sci 123:3052-60 |
| Pavlath, Grace K (2010) Spatial and functional restriction of regulatory molecules during mammalian myoblast fusion. Exp Cell Res 316:3067-72 |
| Griffin, Christine A; Kafadar, Kimberly A; Pavlath, Grace K (2009) MOR23 promotes muscle regeneration and regulates cell adhesion and migration. Dev Cell 17:649-61 |
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