Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA.
Health Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
J Dent Res. 2021 Mar;100(3):283-292. doi: 10.1177/0022034520962463. Epub 2020 Oct 17.
Healthy aging is a complex biological process with progressive accumulation of senescent cells characterized by stable cell cycle arrest, resulting in impaired homeostasis, regenerative potential, and gradual functional decline in multiple tissues and organs, whereby the aberrant activation of mammalian target of rapamycin (mTOR) signaling networks plays a central role. Herein, we explored the effects of extracellular vesicles (EVs) released by gingiva-derived mesenchymal stem cells (GMSC-EVs) on oxidative stress-induced cellular senescence in human endothelial cells and skin fibroblasts and their antiaging potentials. Our results showed that GMSC-EVs robustly abrogated oxidative stress-induced upregulation in the expression of cellular senescence-related genes, such as β-galactosidase, p21, p53, and γH2AX, and mTOR/pS6 signaling pathway, in human umbilical vein endothelial cells (HUVECs) and skin fibroblasts. Meanwhile, GMSC-EVs restored oxidative stress-induced impairment in proliferation and tube formation by HUVECs. Systemic administration of GMSC-EVs attenuated aging-associated elevation in the expression levels of p21, mTOR/pS6, interleukin 6, and tumor necrosis factor α in skin and heart tissues of aged mice. These findings suggest that GMSC-EVs could be a potential alternative source of cell-free product for attenuation of aging-related skin and vascular dysfunctions due to their potent inhibitory effects on oxidative stress-induced cellular senescence in endothelial cells and skin fibroblasts.
健康衰老（Healthy aging）是一个复杂的生物学过程，其特征是衰老细胞的进行性积累，衰老细胞表现为稳定的细胞周期停滞，导致体内平衡受损、再生潜力丧失以及多个组织和器官的功能逐渐下降，其中哺乳动物雷帕霉素靶蛋白（mTOR）信号网络的异常激活起着核心作用。在此，我们探讨了牙龈间充质干细胞（gingiva-derived mesenchymal stem cells，GMSC）来源的细胞外囊泡（extracellular vesicles，EVs）对人内皮细胞和皮肤成纤维细胞氧化应激诱导的细胞衰老及其抗衰老潜能的影响。结果表明，GMSC-EVs 可显著抑制氧化应激诱导的人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVEC）和皮肤成纤维细胞中与细胞衰老相关的基因（如β-半乳糖苷酶、p21、p53 和 γH2AX）以及 mTOR/pS6 信号通路的上调。同时，GMSC-EVs 恢复了氧化应激诱导的 HUVEC 增殖和管形成能力的损伤。系统给予 GMSC-EVs 可减轻衰老小鼠皮肤和心脏组织中 p21、mTOR/pS6、白细胞介素 6 和肿瘤坏死因子 α 等衰老相关基因表达水平的升高。这些发现表明，GMSC-EVs 可能是一种潜在的无细胞产品替代来源，可用于减轻与衰老相关的皮肤和血管功能障碍，因为其对内皮细胞和皮肤成纤维细胞中氧化应激诱导的细胞衰老具有强大的抑制作用。
