Macrophage and fibro-adipogenic progenitor (FAP) communication in skeletal muscle regeneration: Tissue homeostasis and pathogenic remodeling

Skeletal muscle regeneration depends on coordinated interactions between macrophages, fibro-adipogenic progenitors (FAPs), and muscle stem cells (MuSCs). Following injury, macrophages transition from pro-inflammatory to anti-inflammatory phenotypes, regulating debris clearance, cytokine secretion, and the activity of FAPs and MuSCs. FAPs transiently support MuSC-mediated regeneration but, if not cleared appropriately, differentiate into fibroblasts or adipocytes, contributing to fibrosis and fatty infiltration. Dysregulated macrophage-FAP crosstalk drives pathological conditions, including Duchenne Muscular Dystrophy (DMD) and age-related sarcopenia, where imbalances in cytokines and growth factors exacerbate maladaptive remodeling. FAP-derived colony-stimulating factor 1 (CSF1) sustains macrophage survival while macrophage-derived signals, including tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), regulate FAP apoptosis, proliferation, and differentiation, shaping the regenerative niche. Single-cell and spatial transcriptomic approaches have revealed extensive heterogeneity among resident and infiltrating macrophages and FAP subsets, uncovering the molecular circuits underlying intercellular communication. Therapeutic strategies targeting cytokines and growth factors show promise in restoring balanced macrophage-FAP signaling, enhancing regeneration, and limiting fibrosis and fatty infiltration. Understanding the temporal dynamics of macrophage-FAP interactions is essential for developing interventions that preserve muscle homeostasis and counteract degenerative disease.