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. 2020 Nov;235(11):8010-8022.
doi: 10.1002/jcp.29456. Epub 2020 Jan 20.

Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair

Xiaolin Liu  1 , Xin Li  2   3 , Wenwu Zhu  1 , Yuelin Zhang  2   3 , Yimei Hong  2   3 , Xiaoting Liang  4 , Baohan Fan  1 , Hongyan Zhao  1 , Haiwei He  2   3 , Fengxiang Zhang  1
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Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair

Xiaolin Liu et al. J Cell Physiol. 2020 Nov.

Abstract

Accumulating evidence has shown that mesenchymal stem cell (MSC)-derived exosomes (exo) mediate cardiac repair following myocardial infarction (MI). Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, plays a critical role in regulating cell homeostasis. This study aimed to investigate the cardioprotective effects of exo secreted from bone marrow-MSCs (BM-MSCs) overexpressing MIF in a rat model of MI. MIF plasmid was transducted in BM-MSCs. Exo were isolated from the supernatants of BM-MSCs and MIF-BM-MSCs, respectively. The morphology of mitochondria in neonatal mice cardiomyocytes (NRCMs) was determined by MitoTracker staining. The apoptosis of NRCMs was examined by deoxynucleotidyl transferase-mediated dUTP nick end-labeling. BM-MSC-exo and MIF-BM-MSC-exo were intramuscularly injected into the peri-infarct region in a rat model of MI. The heart function of rats was assessed by echocardiography. The expression of MIF was greatly enhanced in MIF-BM-MSCs compared with BM-MSCs. Both BM-MSC-exo and MIF-BM-MSC-exo expressed CD63 and CD81. NRCMs treated with MIF-BM-MSC-exo exhibited less mitochondrial fragmentation and cell apoptosis under hypoxia/serum deprivation (H/SD) challenge than those treated with BM-MSC-exo via activating adenosine 5'-monophosphate-activated protein kinase signaling. Moreover, these effects were partially abrogated by Compound C. Injection of BM-MSC-exo or MIF-BM-MSC-exo greatly restored heart function in a rat model of MI. Compared with BM-MSC-exo, injection of MIF-BM-MSC-exo was associated with enhanced heart function, reduced heart remodeling, less cardiomyocyte mitochondrial fragmentation, reactive oxygen species generation, and apoptosis. Our study reveals a new mechanism of MIF-BM-MSC-exo-based therapy for MI and provides a novel strategy for cardiovascular disease treatment.

Keywords: apoptosis; cardiomyocytes; exosome; macrophage migration inhibitory factor; mesenchymal stem cells; myocardial infarction.

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