Macrophage and fibro-adipogenic progenitor communication in skeletal muscle regeneration: tissue homeostasis and pathogenic remodeling

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