Within the skeletal muscle, Pax7+ satellite cells (SCs) are a quiescent muscle stem cell population that becomes activated upon injury and gives rise to progenitors that migrate, divide, and fuse to generate new muscles. Our understanding for these processes during muscle regeneration is incomplete. The central hypothesis of this proposal is that SCs utilize integrin signaling for specialized functions. SCs are located on the muscle fiber surface and surrounded by the extracellular matrix (ECM). The primary ECM binding receptors on the cell surface are the integrin heterodimers, composed of one a-integrin and one ?-integrin. Integrins anchor cells to the ECM and tether to the actin cytoskeleton. Upon binding to the ECM, integrins signal intracellularly, frequently in concert with growth factor receptors. SCs express many integrins, and they need to be studied systematically to understand SC biology. This proposal is the beginning of a long-term plan to explore how integrins integrate themselves into specific aspects of SC function:
Aim 1 : To tease out ?1-integrin-regulated signaling in SC function: We will determine how ?1-integrin's downstream effectors enhance SC proliferation and self-renewal, via cooperation with FGF2, and potentially with Wnt7a.
Aim 2 : To determine the role of ?3-integrin in SC function: Both ?3- and ?1-integrins can form receptors for the ECM component fibronectin, which has a role in muscle regeneration. We will determine ?3-integrin's function in the SC.
Aim3 : To determine the role of ILK in SC function in vivo: ILK (integrin linked kinase) is present at the basal membrane of SCs as ?1-integrin. We will decipher the role of ILK in the SC. We will also determine whether and how ILK plays a role in integrin-FGF2 synergy in SCs. .
We are interested in how integrin signaling regulates muscle stem cell function. Our recent study of ?1-integrin in the muscle stem cell reveals its essential role for stem cell aging, quiescence, proliferation, self-renewal, migration, and cell fusion. To gain in depth understanding of integrin signaling, we propose to investigate the role of ?3-integrin and integrin linked kinase in muscle stem cells. Results from our research should provide insight into how integrin signaling controls muscle stem cell function, and potential therapeutic targets to enhance muscle regeneration.
