Senescent skeletal muscle fibroadipogenic progenitors recruit and promote M2 polarization of macrophages

Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age‐associated accumulation of immune cells in skeletal muscle. In this study, through cell–cell communication analysis of skeletal muscle single‐cell RNA‐sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs in vitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation‐ and etoposide‐induced senescence. Compared to non‐senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an in vitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages. Through bioinformatic analysis of single‐cell RNA‐sequencing data, we identified unique communication patterns between senescent fibroadipogenic progenitors (FAPs) and macrophages in skeletal muscle of old mice. Using an in vitro model, we demonstrate senescent skeletal muscle‐derived FAPs effectively recruit macrophages, in part, by secretion of the chemokine (C‐X‐C motif) ligand 2 (CCL2) and osteopontin (OPN). Finally, we show the robust secretome of senescent FAPs promotes M2 polarization of macrophages, the subtype evident in skeletal muscle of older mice and humans.