Compromised osteogenic effect of exosomes internalized by senescent bone marrow stem cells via endocytoses involving clathrin, macropinocytosis and caveolae.
Compromised osteogenic effect of exosomes internalized by senescent bone marrow stem cells via endocytoses involving clathrin, macropinocytosis and caveolae.
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DOI：
10.3389/fbioe.2022.1090914
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发表时间：
2022
影响因子：
5.7
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
--
作者：
Qi, Lei;Ge, Weiwen;Pan, Cancan;Jiang, Weidong;Lin, Dan;Zhang, Lei
干细胞衰老导致进行性功能下降，破坏骨环境的生理稳态。干细胞来源的外泌体正在成为治疗多种衰老相关骨疾病的有前景的治疗方法。本研究以骨诱导性外泌体（OI-exo）作为骨修复治疗剂，探讨其在衰老骨髓干细胞（BMSCs）中的内化机制。结果表明，OI-exos可以部分挽救年轻BMSCs的增殖、成骨分化和延缓衰老。在老龄大鼠颅骨缺损模型中，载氧介孔生物活性玻璃（MBG）支架可有效促进体内成骨。然而，OI-exo在体外和体内的成骨作用在衰老个体和老化BMSC中与年轻人相比受到损害。这项研究表明，非衰老的BMSC内化外泌体完全通过网格蛋白介导的内吞作用，而衰老的BMSC另外诱发巨胞饮和小窝介导的内吞作用来介导外泌体的内化。衰老骨髓基质细胞内吞方式的改变和巨胞饮的参与可能是治疗性外泌体作用受损的原因。这项研究中发现的现象也可以扩展到药物或治疗对老年人产生影响的其他情况。在未来的老年人群治疗设计中应考虑内吞方式的影响，避免巨胞饮相关的负面影响。
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 in vitro. OI-exo-delivered hierarchical mesoporous bioactive glass (MBG) scaffold effectively promote in vivo bone formation in aging rat cranial defect model. However, the osteogenic effects of OI-exo both in vitro and in vivo were compromised in senescent individuals and for aging BMSCs compared to younger ones. This study revealed that non-senescent BMSCs internalized exosomes exclusively via 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.
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