Compromised osteogenic effect of exosomes internalized by senescent bone marrow stem cells via endocytoses involving clathrin, macropinocytosis and caveolae

Frontiers in Bioengineering and Biotechnology

Bioengineering and Biotechnology

Lei Qi¹  Lei Zhang¹  Weiwen Ge¹  Cancan Pan¹  Weidong Jiang¹  Dan Lin² 

[1] 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;

关键词: exosomes;    bone marrow stem cells;    senescence;    bone regeneration;    endocytosis;    osteogenic differentiation;   

DOI  :  10.3389/fbioe.2022.1090914

 received in 2022-11-06, accepted in 2022-12-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Qi, Ge, Pan, Jiang, Lin and Zhang.