Mechanobiological response of tendon stem cells: Implications of tendon homeostasis and pathogenesis of tendinopathy

Tendons are constantly subjected to mechanical loading in vivo. Recently, stem cells were identified in human, mouse, and rabbit tendons, but the mechanobiological responses of tendon stem cells (TSCs) are still undefined. Using an in vitro system capable of mimicking in vivo loading conditions, it was determined that mechanical stretching increased TSC proliferation in a stretching magnitude-dependent manner. Moreover, low mechanical stretching at 4% ("clamp-to-clamp" engineering strain) promoted differentiation of TSCs into tenocytes, whereas large stretching at 8% induced differentiation of some TSCs into adipogenic, chondrogenic, and osteogenic lineages, as indicated by upregulated expression of marker genes for adipocytes, chondrocytes, and osteocytes. Thus, low mechanical stretching may be beneficial to tendons by enabling differentiation of TSCs into tenocytes to maintain tendon homeostasis. However, large mechanical loading may be detrimental, as it directs differentiation of TSCs into non-tenocytes in tendons, thus resulting in lipid accumulation, mucoid formation, and tissue calcification, which are typical features of tendinopathy at later stages.