Extracellular vesicles from antler blastema progenitor cells reverse bone loss and improve aging-related phenotypes in mice and macaques [RNA-seq]

Antler blastema progenitor cell (ABPC) is a novel type of skeletal mesenchymal stem cell with strong stemness and renewal ability. Here, we discovered that ABPC-derived extracellular vesicles (EVsABPCs) can strongly rejuvenate aging tissues in aged mice and rhesus macaques (Macaca mulattas). We identified a variety of rejuvenating molecules in EVsABPCs that differed from EVs of mouse bone marrow stromal stem cells (EVsBMSCs). EVsABPCs exhibited a robust in vitro ability to rejuvenate senescence BMSCs of aged mice and shift their molecular signature into a youthful state. In vivo, EVsABPCs increased bone mineral density in the femur by 2.4-fold in mice, and 1.53-fold in rhesus macaques. Besides, intravenous EVsABPCs significantly outperformed mouse fetal-EVsBMSCs in improving physical performance, reducing systemic inflammation, and rejuvenating major tissues of elderly mice, with no observed immunological side effects. Furthermore, EVsABPCs showed similar rejuvenating effects in old rhesus macaques as in elderly mice. Particularly, EVsABPCs resulted in remarkable improvements in brain structure and behaviors of elderly rhesus macaques, providing the first batch of evidence of EVs’ beneficial effects on aging brains in primates. These findings suggest that the ABPC is a novel and practical source of EVs containing a wealth of systemic rejuvenating factors and has considerable translational value for anti-aging interventions, particularly the rejuvenation of aging bones.鹿角芽基祖细胞（Antler blastema progenitor cell, ABPC）是一类具备强干细胞特性与自我更新能力的新型骨骼间充质干细胞。本研究发现，ABPC来源的细胞外囊泡（EVsABPCs）可强效促使衰老小鼠与恒河猴（Macaca mulattas）的衰老组织实现年轻化。我们在EVsABPCs中鉴定出多种与小鼠骨髓基质干细胞来源细胞外囊泡（EVsBMSCs）不同的年轻化相关分子。体外实验结果显示，EVsABPCs可显著逆转衰老小鼠骨髓基质干细胞的衰老状态，并将其分子特征重塑为年轻化状态。体内实验中，EVsABPCs可使小鼠股骨骨密度提升2.4倍，恒河猴股骨骨密度提升1.53倍。此外，静脉注射EVsABPCs在改善老年小鼠体能、减轻全身性炎症、促使主要组织年轻化方面，显著优于小鼠胎儿来源的EVsBMSCs，且未观察到免疫相关副作用。进一步研究表明，EVsABPCs在老年恒河猴中展现出与老年小鼠中一致的组织年轻化效果。尤为关键的是，EVsABPCs可显著改善老年恒河猴的大脑结构与行为表现，首次提供了灵长类动物细胞外囊泡对衰老大脑具有有益作用的实证依据。上述研究结果表明，ABPC是一类富含系统性年轻化因子的新型实用细胞外囊泡来源，在抗衰老干预尤其是衰老骨骼年轻化领域具备极高的转化应用价值。