Secretome Profiling of Young Multipotent Stem Cells Reveals Angiogenic and Immunomodulatory Mechanisms Supporting Aged Neuromuscular Health

Aging is the primary risk factor for many neuromuscular (NM) diseases that impair motor and cognitive function. Transplantation of young muscle-derived stem/progenitor cells (MDSPCs) has shown remarkable therapeutic potential across a range of age-related diseases, primarily through paracrine mechanisms. In this study, secretome profiling of young MDSPCs revealed a unique enrichment of pro-angiogenic and immunomodulatory proteins compared to their aged counterparts. Our systemic transplantation experiments also demonstrate that young MDSPCs activate biological pathways linked to these secreted factors, providing strong mechanistic evidence of their contribution to the reversal of age-associated NM decline at molecular, structural, and functional levels. Systemic transplantation of young MDSPCs into naturally aged mice enhanced motor function and reduced anxiety-like behavior. Structural improvements in aged NM tissues were partially mediated by phosphorylating protein sites involved in muscle neovascularization and regulation of blood-brain barrier integrity in the motor cortex. Paracrine signaling from young MDSPCs enhanced the endogenous regenerative capacity of aged tissues, with effects sustained for up to 2 months post-transplantation. Overall, this study elucidates the molecular basis of MDSPC-mediated NM rejuvenation and provides a foundation for developing novel protein-based therapies to combat age-related functional decline.