Qi Lei, Ge Weiwen, Pan Cancan, Jiang Weidong, Lin Dan, Zhang Lei
Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.
Shanghai University of Medicine and Health Sciences, Shanghai, China.
Front Bioeng Biotechnol. 2023 Jan 4;10:1090914. doi: 10.3389/fbioe.2022.1090914. eCollection 2022.
Stem cell senescence leads to progressive functional declines and disrupts the physiological homeostasis of bone environment. Stem cell-derived exosomes are emerging as promising therapeutical approaches to treat diverse aging-related osseous diseases. Herein, a previously reported osteoinductive exosome (OI-exo) was applied as a therapeutic agent for bone repair in aging individuals and its internalization mechanisms in senescent bone marrow stem cells (BMSCs) were explored. The results demonstrated that OI-exos derived from young BMSCs could partially rescue the proliferation, osteogenic differentiation and alleviate aging phenotypes . OI-exo-delivered hierarchical mesoporous bioactive glass (MBG) scaffold effectively promote bone formation in aging rat cranial defect model. However, the osteogenic effects of OI-exo both and were compromised in senescent individuals and for aging BMSCs compared to younger ones. This study revealed that non-senescent BMSCs internalized exosomes exclusively clathrin-mediated endocytosis, while senescent BMSCs additionally evoked macropinocytosis and caveolae-mediated endocytosis to mediate the internalization of exosomes. The alteration of endocytic manner of senescent BMSCs and the involvement of macropinocytosis might be responsible for the compromised effects of therapeutical exosomes. The phenomena discovered in this study could also be extended to other scenarios where drugs or treatments exerted compromised effects in aging individuals. The influence of endocytic manner, avoidance of macropinocytosis-related negative effects should be taken into considerations in future therapeutic design for aging populations.
干细胞衰老导致功能逐渐衰退，并破坏骨环境的生理稳态。干细胞衍生的外泌体正成为治疗多种衰老相关骨疾病的有前景的治疗方法。在此，将先前报道的骨诱导外泌体（OI-exo）用作衰老个体骨修复的治疗剂，并探索其在衰老骨髓干细胞（BMSC）中的内化机制。结果表明，源自年轻BMSC的OI-exo可以部分挽救增殖、成骨分化并减轻衰老表型。OI-exo递送的分级介孔生物活性玻璃（MBG）支架有效地促进了衰老大鼠颅骨缺损模型中的骨形成。然而，与年轻个体相比，OI-exo在衰老个体和衰老BMSC中的成骨作用均受到损害。这项研究表明，非衰老BMSC仅通过网格蛋白介导的内吞作用内化外泌体，而衰老BMSC还会引发巨胞饮作用和小窝介导的内吞作用来介导外泌体的内化。衰老BMSC内吞方式的改变和巨胞饮作用的参与可能是治疗性外泌体效果受损的原因。本研究中发现的现象也可以扩展到药物或治疗在衰老个体中效果受损的其他情况。在未来针对老年人群体的治疗设计中，应考虑内吞方式的影响，避免巨胞饮作用相关的负面影响。
