Zhang Hao, Zhao Chengling, Jiang Guojun, Hu Bei, Zheng Huifeng, Hong Yimei, Cui Zhen, Shi Linli, Li Xin, Lin Fang, Ding Yue, Wei Lu, Li Mimi, Liang Xiaoting, Zhang Yuelin
Faculty of Pharmacy, Bengbu Medical College, Bengbu, China.
Department of Emergency Medicine, Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Front Cell Dev Biol. 2021 Mar 2;9:628463. doi: 10.3389/fcell.2021.628463. eCollection 2021.
The protective effects of mesenchymal stem cell (MSC)-based therapy for myocardial infarction (MI) are largely hampered as they age. Apelin is an endogenous ligand of its receptor APJ and plays an essential role in regulating multiple biological activities including MSC proliferation and survival. In this study, we investigated whether Apelin regulates MSC senescence and whether its overexpression could rejuvenate aged MSCs (AMSCs) to improve cardiac protection following infarction in mice. MSC senescence was evaluated by senescence-associated β-galactosidase assays. Apelin level was examined by western blotting. Autophagy was determined by transmission electron microscopy. The cardioprotective effect of AMSCs with Apelin overexpression (Apelin-AMSCs) was assessed in a mouse MI model. Apelin expression was dramatically reduced in AMSCs. Interestingly, knockdown of Apelin induced young MSCs (YMSC) senescence, whereas overexpression rescued AMSC senescence. Apelin overexpression also increased AMSC angiogenic capacity. Mechanistically, Apelin overexpression upregulated the autophagy level of AMSCs by activating AMP-activated protein kinase (AMPK) signaling, thereby rejuvenating AMSCs. Compared with AMSCs, transplantation of Apelin-AMSCs achieved better therapeutic efficacy for MI by enhancing cell survival and angiogenesis. In conclusion, our results reveal that Apelin activates AMPK to rejuvenate AMSCs by increasing autophagy and promotes cardioprotection following infarction in mice. This study identified a novel target to rejuvenate AMSCs and enhance their therapeutic efficacy.
基于间充质干细胞（MSC）的心肌梗死（MI）治疗随着细胞老化，其保护作用受到很大阻碍。Apelin是其受体APJ的内源性配体，在调节包括MSC增殖和存活在内的多种生物学活性中起重要作用。在本研究中，我们调查了Apelin是否调节MSC衰老，以及其过表达是否能使衰老的MSC（AMSC）恢复活力，以改善小鼠梗死后的心脏保护作用。通过衰老相关β-半乳糖苷酶检测评估MSC衰老。通过蛋白质免疫印迹法检测Apelin水平。通过透射电子显微镜确定自噬情况。在小鼠MI模型中评估过表达Apelin的AMSC（Apelin-AMSC）的心脏保护作用。Apelin在AMSC中的表达显著降低。有趣的是，敲低Apelin诱导年轻MSC（YMSC）衰老，而过表达则挽救了AMSC衰老。Apelin过表达还增加了AMSC的血管生成能力。机制上，Apelin过表达通过激活AMP激活的蛋白激酶（AMPK）信号上调AMSC的自噬水平，从而使AMSC恢复活力。与AMSC相比，Apelin-AMSC移植通过增强细胞存活和血管生成对MI实现了更好的治疗效果。总之，我们的结果表明，Apelin通过增加自噬激活AMPK使AMSC恢复活力，并促进小鼠梗死后的心脏保护作用。本研究确定了一个使AMSC恢复活力并提高其治疗效果的新靶点。
