Apoptotic BMSCs-Derived Extracellular Vesicles Promote Bone Repair Via Activating the ROS-Induced JNK Signal

The transplantation of bone marrow mesenchymal stem cells (BMSCs) promotes bone repair and regeneration. However, it has been shown that the majority of BMSCs die within a short period after transplantation. During apoptosis, BMSCs generate a large number of apoptotic cell-derived extracellular vesicles (ApoEVs). This study aims to understand the potential role of ApoEVs in bone defect repair and regeneration. We confirm that BMSCs undergo apoptosis 2 days after transplantation into the defect of the cranium. In vitro, we find that abundant ApoEVs were generated by apoptotic BMSCs and can be engulfed by BMSCs and promote the proliferation, migration, and osteogenic differentiation of recipient cells. ApoEVs from cells in the middle stage of apoptosis were the most efficient at enhancing the regeneration capacity of BMSCs. In vivo, transplantation of ApoEVs in the calvarial defect region significantly promoted bone regeneration in both mouse and rat models. Mechanistically, ApoEVs promote new bone formation by upregulating the Reactive Oxygen Species (ROS) and activating the JNK signaling. This study reveals a previously unknown role of the dying transplanted BMSCs in promoting the viability of endogenous BMSCs and repairing the bone defects. Since it could avoid several adverse effects and limits of BMSCs cytotherapy, treatment of ApoEVs might be a promising strategy in bone repair and regeneration.