Mesenchymal Stromal Cell‐Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration

ABSTRACT Mesenchymal stromal cells (MSCs) support tissue homeostasis and regeneration, yet their molecular signals remain largely enigmatic. In skeletal muscle (SkM), MSCs, known as fibroadipogenic progenitors (FAPs), are essential for maintenance and repair, orchestrating these processes through intricate cellular communication networks. Given the critical role of SkM in lifelong health and longevity, FAP signaling has drawn significant interest as a potential therapeutic target and a model for MSC interactions. However, deciphering FAP‐derived regulatory signals remains challenging due to their pleiotropic complexity. Here, we employ a systems‐level approach to construct a comprehensive FAP interactome in both homeostatic and regenerating SkM. By integrating unique single‐cell RNA sequencing atlases with advanced computational analyses, we identify putative FAP‐mediated signaling pathways and validate their biological relevance through FAP depletion experiments, assessing disruptions in key pathways. This approach reveals novel signaling networks across diverse SkM cell populations, corroborates key FAP interactions from recent studies, and provides a valuable dataset for modeling MSC interactions and their roles in SkM homeostasis and regeneration.