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

Abstract

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 magnitudedependent 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. Tendons transmit muscular forces to bone and are constantly subjected to mechanical loading in vivo. As such, tendons are susceptible to pathological changes, known as tendinopathy. Tendinopathy is especially prevalent in both occupational and athletic settings that involve repetitive motions, indicating that excessive mechanical loading placed on tendons is a major contributor to the development of tendinopathy. Nevertheless, the precise pathogenic mechanisms of tendinopathy remain unclear. However, the typical histopathological features of tendinopathy have been identified, including accumulation of lipid cells, mucoid degeneration, tissue calcification, or some combination thereof.1 These findings suggest that tendons contain cells with the potential to exhibit multi-phenotypes that differ from tenocytes, the resident cells in tendons, which express the fibroblast phenotype. Indeed, tendon stem/progenitor cells (TSCs) were recently identified from humans, mice, and rabbits, and TSCs were shown to have multi-differentiation potential. These stem cells can differentiate into non-tenocyte lineages such as adipocytes, chondrocytes, and osteocytes. 2,3 Stem cells are able to perpetuate themselves through self-replication and differentiation, a process which generates mature cells of a particular tissue. Currently, most studies in stem cell research focus on isolation, identification, and characterization of stem cells. Few studies have investigated the effects of mechanical loading on stem cells, which is nevertheless essential for gaining a better understanding of the physiology and pathology of load-bearing tissues such as tendons. 4 Existing studies, however, have indicated that mechanical loading regulates stem cell proliferation and differentiation. For example, mechanical stretching stimulates proliferation of human bone marrow mesenchymal ste...

The Role of Mechanical Loading in Tendon Development, Maintenance, Injury, and Repair

“…Tissue engineers are incorporating mechanical stimulation to enhance tendon tissue augmentations and replacements [134][135][136][137][138][139][140][141][142][143][144][145][146] . By mechanically preconditioning the tissue-engineered construct cell population prior to in vivo implantation, the cells may be better equipped to enhance the repair since they have been exposed to the appropriate mechanical environment 134,135 .…”

“…Given the importance of physiological loading to maintain tendon homeostasis, investigators have shown that applying load promotes a tendon-like phenotype in both two and threedimensional culture conditions [139][140][141][142][143][144][145][146] . Ralphs et al showed that when tendon cells are cultured on a two-dimensional substrate and subjected to biaxial strain at 1 Hz for eight hours per day for a total of ninety-six hours, cells link together using actin adherens junctions along the principal line of strain to monitor tensile load 142 .…”

The Achilles Tendinopathy: Pathogenesis Review

“…Concluding this analisys of the effects of overuse on tendons, it must be remembered that recent studies found tendon stem cells (TSCs) in human and animal tendon tissue [122,123] . Effects on mechanical loading on TSCs have been investigated on both in vivo and in vitro models [22,124] ; findings from these studies suggest that TSCs undergo loading magnitude-dependent differentiation: under large mechanical stress TSCs differentiate into nontenocytes, such as adipocytes, chondrocyte and osteocytes [125] . Such nontenocyte differentiation may explain the histopathological features of tendinopathy at later stages (tendinosis patterns of degeneration: hypoxic, mucoid or mixoid, hyaline, fatty, fibrinoid, calcific, or some combination of these [58] ).…”

Higher BMP receptor expression and BMP-2-induced osteogenic differentiation in tendon-derived stem cells compared with bone-marrow-derived mesenchymal stem cells

“…It is not known whether Smad proteins and MSX2 also function to inhibit osteogenic differentiation and promote TDSC tenogenic differentiation, as reported in previous studies [30,32,34]; further study is required. Other factors, such as mechanical loading [35] and local extracellular matrix environment [9], may also function to suppress TDSC osteogenesis inside the tendon midsubstance. For instance, Zhang et al reported that low mechanical stretching promoted tendon stem cell differentiation into tenocytes, whereas large stretching induced differentiation of some tendon stem cells into adipogenic, chondrogenic and osteogenic lineages [35].…”

“…Other factors, such as mechanical loading [35] and local extracellular matrix environment [9], may also function to suppress TDSC osteogenesis inside the tendon midsubstance. For instance, Zhang et al reported that low mechanical stretching promoted tendon stem cell differentiation into tenocytes, whereas large stretching induced differentiation of some tendon stem cells into adipogenic, chondrogenic and osteogenic lineages [35]. Biglycan and fibromodulin depletion in a double knockout animal model has shown increased TPSC sensitivity to BMP-2 signalling and tendon ossification, suggesting that normal biglycan and fibromodulin levels might have roles in regulating the BMP-2 signalling pathway in TPSCs [9].…”