Apoptotic vesicles rejuvenate mesenchymal stem cells via Rab7-mediated autolysosome formation and alleviate bone loss in aging mice
Fangcao Lei, Zhiqing Huang, Qianmin Ou, Jiaqi Li, Manqing Liu, Lan Ma, Lingping Tan, Zhengmei Lin, Xiaoxing Kou
Abstract
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.