Abstract
Tendon stem cells (TSCs) are often exposed to oxidative stress at tendon injury sites, which impairs their physiological effect as well as therapeutic application. Recently, extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) were shown to mediate cell protection and survival under stress conditions. The function of BMSC-EVs may be affected by pretreatment with various factors such as eugenol (EUG)—a powerful antioxidant. In our previous study, we found that H2O2 significantly impaired TSC proliferation and tenogenic differentiation capabilities. Apoptosis and intracellular ROS accumulation in TSCs were induced by H2O2. However, such H2O2-induced damage was prevented by treatment with EUG-BMSC-EVs. Furthermore, EUG-BMSC-EVs activated the Nrf2/HO-1 pathway to counteract H2O2-induced damage in TSCs. In a rat patellar tendon injury model, the ROS level was significantly higher than that in the normal tendon and TSCs not pretreated showed a poor therapeutic effect. However, EUG-BMSC-EV-pretreated TSCs significantly improved tenogenesis and matrix regeneration during tendon healing. Additionally, the EUG-BMSC-EV group had a significantly improved fiber arrangement. Overall, EUG-BMSC-EVs protected TSCs against oxidative stress and enhanced their functions in tendon injury. These findings provide a basis for potential clinical use of EUG-BMSC-EVs as a new therapeutic vehicle to facilitate TSC therapies for tendon regeneration.
Highlights
Tendons play important roles in transmitting forces from muscles to the skeleton
Western blotting analysis revealed that the expression levels of CD9, HSP70, and TSG101 were significantly higher in extracellular vesicles (EVs) compared with bone marrow mesenchymal stem cells (BMSCs) (Figure 1(f))
We found that EVs derived from EUG-preconditioned BMSCs can significantly enhance tendon stem cells (TSCs) capability in tendon injury compared with BMSC-EVs
Summary
Tendons play important roles in transmitting forces from muscles to the skeleton. They are frequently injured by mechanical loading during both occupational and gymnastic activities [1]. The healing process of tendons is slow because of the inability of tendons to self-repair and the poor regenerative capability of tenocytes [2]. Tenocyte- and mesenchymal stromal cell-based therapeutic strategies have been applied to tendon injuries [3,4,5]. Tenocytes and mesenchymal stromal cells may not be ideal cell sources for tendon repair because of their limited proliferative capability and the risk of ectopic bone formation [6]. Nontenocyte differentiation and TSC dysfunction may occur after their transplantation because the local biochemical environment undergoes complicated changes after injuries, such as inflammation and oxidative stress [10, 11]
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