Tendon Stem/Progenitor Cells and Their Interactions with Extracellular Matrix and Mechanical Loading

Abstract

Tendons are unique connective tissues in the sense that their biological properties are largely determined by their tendon-specific stem cells, extracellular matrix (ECM) surrounding the stem cells, mechanical loading conditions placed on the tendon, and the complex interactions among them. This review is aimed at providing an overview of recent advances in the identification and characterization of tendon stem/progenitor cells (TSPCs) and their interactions with ECM and mechanical loading. In addition, the effects of such interactions on the maintenance of tendon homeostasis and the initiation of tendon pathological conditions are discussed. Moreover, the challenges in further investigations of TSPC mechanobiology in vitro and in vivo are outlined. Finally, future research efforts are suggested, which include using specific gene knockout models and single-cell transcription profiling to enable a broad and deep understanding of the physiology and pathophysiology of tendons.

In Vitro Innovation of Tendon Tissue Engineering Strategies

“…Tendon development, homeostasis, pathology, and injury healing are driven by applied mechanical loads [93]. Mechanical forces are translated, by means of mechanotransduction processes, into biochemical signals that are able to activate and control key signaling pathways into tendon cells [94,95].…”

“…TSPCs express higher mRNA levels of tendon-related gene markers including the transcription factor Scx and the late differentiation factor Tnmd [214]. TSPCs spontaneously undergo tenocyte differentiation in vitro [215] and exposure to tendon ECM component in vitro, such as biglycan; they also enhance TSPCs differentiation into tenocytes, as they express late tendon-specific markers such as thrombospondin 4 and tenomodulin at gene and protein levels [93].…”

“…This means that tenocytes can be anticipated to live in a physiological low O 2 environment [237]; thus, a lower oxygen tension appears to be critical for tendon recovery and remodeling in vivo or for the preservation of resident cells phenotype ex vivo. The two major types of cells contained in tendons are tenocytes and the recently isolated tendon stem cells (TSCs) [93], which can promote tendon repair [238].…”

Extracellular HMGB-1 activates inflammatory signaling in tendon cells and tissues

“…2,7,9 Our previous studies have confirmed the presence of HMGB-1 in tendon cells and tissues, while the ECM of normal tendon tissues contains almost no HMGB-1. 9,23,24 We also found that HMGB-1 can be secreted from tendon cells to the extracellular space when stimulating the tendon tissues with mechanical overloading. 9 In the current study, we have shown that exogenous HMGB-1 actively promotes the induction of inflammation-related gene expressions, such as TNF-α and IL-6, and catabolic responders involved in tissue remodeling, such as MMP-3 and MMP-13.…”

The Role of Scaffolds in Tendon Tissue Engineering

“…Mechanical signal transduction through molecular signaling triggers tendon adaptive responses in mechanical loads [12]. However, the overloading of a tendon, either by exceeding its maximum strain or by providing insufficient recovery time between repetitive sprains can cause damage to the collagen network, which is widely associated with a decrease in quality of life [1,2,12]. The structure and composition of the tendons are responsible for their unique mechanical properties, reflected by four distinct regions of the stress/strain curve.…”