PROJECT SUMMARY Aging of skeletal muscle results in sarcopenia. It is believed that sarcopenia is in part due to a decreased capacity of stem cells, namely satellite cells, to repair the skeletal muscle after injury. Satellite cells are the major source of myogenic progenitors for adult muscle homeostasis and repair. A potential alternative for dysfunctional satellite cells is induced pluripotent stem cells (iPSC) which have the capacity to differentiate into skeletal muscle myocytes and blood vessels. Here, we have identified a highly efficient small molecule, givinostat (Givi), a histone deacetylase inhibitor (HDACi) which is capable of transforming human iPSC into myogenic progenitor cells (MPC) that are highly proliferative and generate large numbers of extracellular vesicles (EV). Our ?pharmacological reprogramming? approach using small molecules to generate MPC in a limited period of time and without use of viral vectors is a very significant step forward in cell-based therapy. We are proposing that iPSC pharmacologically reprogrammed into MPC with Givi will be optimally effective to regenerate sarcopenic muscle. In specific aim 1, the hypothesis that induced myogenic progenitor cells (iMPC) from iPSC with novel small molecules are effective and safe for regeneration of aged muscle will be tested; In specific Aim 2, the hypothesis that accelerated mobilization and engraftment of iMPC in an aged muscle microenvironment stimulate muscle regeneration will be tested; In specific Aim 3, the hypothesis that EV derived from Givi-induced MPC rejuvenate aged muscle and augment muscle regeneration will be tested. If many of the regenerative properties of iMPC can be credited to EV, there will be a paradigm shift in regenerative medicine to enable endogenous self-repair in sarcopenia by cell to cell transfer of proteins, mRNAs, and miRNAs (miRs) by EV. EV from engineered or modified stem cells are highly enriched with bioactive molecules including myogenic miRs responsible for activation of signaling pathways important in muscle regeneration. These studies will involve multidisciplinary approaches which will employ state of the art molecular biology, biochemical, histochemical, immunohistochemical techniques and integrative physiology involving well established experimental animal model and muscle function. This proposal is conceptually innovative because it addresses the structural and molecular characterization of iMPC and their EV and tests their role as key biological messengers of iMPC action in the treatment of sarcopenia.
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