No 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.

Bone marrow (BM) is the most common site of neuroblastoma (NB) metastasis, and its involvement represents poor patient prognosis. In accordance with the “seed and soil” theory of tumor metastasis, BM provides a favorable environment for NB metastasis while bone marrow mesenchymal stem cells (BMSCs) have been recognized as a central part of tumor stroma formation. Yet, there is currently no effective method for intervening these BMSCs. We found that BMSCs affected by NB (NB-BMSCs) could significantly promote NB growth and migration. Additionally, tumor cell-endowed BMSCs showed stronger resistance to several chemotherapeutic agents. Surprisingly, NB-BMSCs were more sensitive to ferroptosis than normal BMSCs. NB-BMSCs had lower levels of intracellular free iron while synthesizing more iron-sulfur clusters and heme. Moreover, the Xc¯/glutathione/glutathione peroxidase 4 (Xc¯/GSH/GPX4) pathway of the anti-ferroptosis system was significantly downregulated. Accordingly, ferroptosis inducers erastin and RAS-selective lethal 3 (RSL3) could significantly kill NB-BMSCs with limited effects on normal BMSCs. BMSCs from NB patients with BM metastasis also showed poor anti-ferroptosis ability compared with those from NB patients without BM metastasis. In vivo studies suggested that co-injection of mice with BMSCs and NB cells could significantly promote the growth of tumor tissues compared with injecting NB cells alone. However, treatment with erastin or RSL3 resulted in the opposite effect to some extent. Our results revealed that NB-BMSCs were vulnerable to ferroptosis from downregulation of the Xc¯/GSH/GPX4 pathway. Ferroptosis inducers could effectively kill NB-BMSCs, but not normal BMSCs. This study provides possible new ideas for the treatment of tumor-associated BMSCs in NB patients.