Tendon homeostasis and regeneration: Interplay of cells, immune response, and bioactive compounds

Tendons are specialized connective tissues that transmit mechanical forces from muscle to bone, ensuring joint stability and efficient locomotion. Their homeostasis and regenerative capacity depend on the interplay between extracellular matrix (ECM), resident and recruited cell populations, and immune-mediated signaling. This review provides an overview of tendon structure and composition, emphasizing the collagen-based organization and the functional role of non-collagenous matrix components in mechanotransduction and cell signaling. The heterogeneity of tendon-resident cells, including tenocytes, tendon stem/progenitor cells, and vascular- and immune-associated cells, is discussed, highlighting their roles in tissue maintenance, adaptation, and repair. Tendon aging is characterized by altered cellular responsiveness, ECM disorganization, and reduced capacity to resolve inflammation, predisposing tissues to degeneration and chronic tendinopathies. Emerging evidence underscores the central role of the immune response in both inflammatory and healing processes. Key bioactive compounds used in tendinopathy management, such as collagen, vitamin C, vitamin D, methylsulfonylmethane, hyaluronic acid, and manganese, are discussed regarding their mechanistic effects on collagen synthesis, matrix remodeling, oxidative stress, immune modulation, and cell-matrix interactions. Overall, tendon health emerges from a dynamic balance between structural integrity, cellular activity, and immune regulation, supporting the rationale for targeted nutritional strategies to promote tendon homeostasis and regeneration. • Tendon health relies on cells, matrix, and immune signaling balance. • Tenocyte and progenitor cell heterogeneity supports repair and adaptation. • Dysregulated inflammation drives chronic tendon degeneration. • Bioactive compounds modulate collagen synthesis, matrix remodeling, and immunity. • Nutritional interventions can promote tendon regeneration and health.