Apelin Rejuvenates Aged Human Mesenchymal Stem Cells by Regulating Autophagy and Improves Cardiac Protection After Infarction.

Hao Zhang,Lu Wei,Bei Hu,Zhen Cui,Mimi Li,Xin Li,Guojun Jiang,Huifeng Zheng,Yue Ding,Chengling Zhao,Xiaoting Liang,Yuelin Zhang,Fang Lin,Yimei Hong,Linli Shi

doi:10.3389/fcell.2021.628463

Abstract

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.

Highlights

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide in older adults
We measured the concentration of secreted Apelin in conditioned media (CdM) from young MSCs (YMSC) and aged MSCs (AMSCs)
These results indicate that decreased Apelin expression may affect the regulation of mesenchymal stem cell (MSC) senescence

Summary

Introduction

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide in older adults. Despite significant progress in pharmacological and surgical treatments, existing therapies are not sufficient to improve the clinical outcomes of MI. Preclinical studies and clinical trials in the last decade have demonstrated that mesenchymal stem cells (MSC)-based therapy is a novel strategy for MI treatment due to easy isolation, multilineage differentiation, and low risk of immune rejection (Zhang et al, 2017; Xiao et al, 2018; Liao et al, 2019). There is an urgent need to rejuvenate aged-MSCs (AMSCs) to improve their beneficial effects. Some strategies, including genetic modification and pharmacological pretreatment, are being explored to rejuvenate AMSCs (Song et al, 2017; Liang et al, 2019; Hong et al, 2020).

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Conclusion