VDAC1-enriched apoptotic extracellular vesicles emerge as an autophagy activator orchestrating PDLSC-based bone regeneration

Apoptosis is a programmed cell death process producing a large number of apoptotic extracellular vesicles (ApoEVs), which are involved in multiple pathophysiological states. Periodontal ligament stem cell (PDLSC) transplantation is demonstrated to be an effective approach in bone regeneration, during which, PDLSCs undergo necessary apoptosis rather than differentiation into osteoblasts. However, whether ApoEVs mediate PDLSC transplantation-based bone regeneration and the underlying mechanism remain largely unknown. In this study, we transplanted the GelMA@ PDLSC complex in nude mice, and first uncovered that the PDLSC apoptosis shortly after transplantation is essential for osteogenesis. Based on the transplanted complex at an early stage, plenty of vesicles were observed budding from the PDLSC surface, indicating the involvement of ApoEVs in this process. We then demonstrated ApoEVs secreted by PDLSCs could be endocytosed by bone marrow mesenchymal stem cells (BMSCs) to facilitate their osteogenic differentiation and also bone regeneration in a skull defect model. In terms of mechanism, voltage dependent anion channel protein 1 (VDAC1) enriched in ApoEVs was proved to act as an autophagy activator to enhance the osteogenic differentiation of BMSCs and bone regeneration. The accelerating effect of ApoEVs was impaired when VDAC1 was knocked down. This study not only emphasizes the importance of apoptotic PDLSC and the derived ApoEVs in osteogenesis, but also unmasks the mechanism involved, which may provide new insights and strategies for stem cell-based bone regeneration.