Apoptotic vesicles rejuvenate mesenchymal stem cells via Rab7-mediated autolysosome formation and alleviate bone loss in aging mice

Aging skeletons display decreased bone mass, increased marrow adiposity, and impaired bone marrow mesenchymal stem cells (MSCs). Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles (apoVs). Dysregulated apoptosis has been closely linked to senescence-associated diseases. However, whether apoVs mediate aging-related bone loss is not clear. In this study, we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal, osteo-/adipo-genic lineage differentiation capacities via activating autophagy. Mechanistically, apoptotic young MSCs generated and enriched a high level of Ras-related protein 7 (Rab7) into apoVs. Subsequently, recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation, thereby contributing to autophagy flux activation and MSC rejuvenation. Moreover, systemic infusion of young MSC-derived apoVs enhanced bone mass, reduced marrow adiposity, and recused the impairment of recipient MSCs in aged mice. Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.