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

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.

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

“…Previous studies have shown that autophagy plays a critical role in the senescence of MSCs and that reducing autophagy diminishes the tolerance of stem cells under various stresses [ 35 , 38 , 49 ]. Pre-activation of autophagy with rapamycin was shown to promote the survival of MSCs in the infarcted myocardium [ 33 ].…”

“…Previous studies reviewed the relations between cellular senescence and autophagy [ 30 , 31 ] and suggested that autophagy plays a dual role in the regulation of MSC senescence. Upregulation of autophagy can decrease the apoptosis of aged MSCs in the condition of myocardial infarction [ 34 , 35 ], restore the biological properties of aged MSCs [ 76 ], rejuvenate MSCs derived from patients with idiopathic pulmonary fibrosis [ 49 ], and reduce the senescence of patellar tendon stem/progenitor cells [ 77 ]. Compared with young MSCs, aged MSCs have significantly reduced autophagic activity.…”

“…Accumulated evidence indicates that autophagy is implicated in MSC senescence [ 30 , 31 ]. The upregulation of autophagy could delay stem cell aging [ 32 – 35 ]. In addition, some research has suggested that transplanted MSCs present insufficient autophagy in disease microenvironments [ 36 , 37 ] and that hypoxic preconditioning can improve the autophagy of stem cells [ 38 ].…”

Tumorigenic Aspects of MSC Senescence—Implication in Cancer Development and Therapy

“…Moreover, the engraftment of NDNF-overexpressing old MSCs was shown to improve cardiac function in mice after myocardial infarction [109,110]. Similarly, overexpression of apelin, an endogenous ligand that might be involved in the regulation of MSC senescence, rejuvenated human AT-MSCs by increasing autophagy and promoted cardioprotection following myocardial infarction in mice [111]. Increased expression of macrophage migration inhibitory factor (MIF) also rejuvenated aged human BM-MSCs by activating autophagy and improving their survival under serum deprivation/hypoxia in vitro [112].…”

Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival

“…In a mouse model of hindlimb ischemia, Apelin treatment increased the viability of adipose-derived MSCs by promoting autophagy during hypoxia via activation of the Akt signaling pathway, leading to a better therapeutic efficacy [ 16 ]. Furthermore, overexpression of Apelin rejuvenated the aged-MSCs and enhanced their cardioprotective effects in MI [ 17 ]. Nonetheless, whether pretreatment of Apelin-13 can enhance the survival of MSCs in the ischemic heart and thereby improve cardiac repair and the underlying mechanisms remains unclear.…”