Exosomes derived from cardiac progenitor cells attenuate CVB3-induced apoptosis via abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways

Xin Li,Zuocheng Yang,Zhuoying Li,Xing Ma,Lang Tian,Jie Jiang,Shentang Li,Wenyuan Nie

doi:10.1038/s41419-019-1910-9

Xin Li, Zuocheng Yang + Show 6 more

Open Access

https://doi.org/10.1038/s41419-019-1910-9

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Abstract

Viral myocarditis is potentially fatal and lacking a specific treatment. Exosomes secreted by cardiac progenitor cells (CPCs) have emerged as a promising tool for cardioprotection and repair. In this study, we investigated whether CPCs-derived exosomes (CPCs-Ex) could utilize the mTOR signal pathway to reduce the apoptosis in viral myocarditis. In vitro, exosomes were, respectively, added to H9C2 cells after CVB3 infection to detect the anti-apoptosis effect of CPCs-Ex. Compared with the controls, the apoptosis rate was reduced, accompanied with the depressed expression of viral capsid protein 1 (VP1) and pro-apoptosis factors of Bim/caspase families. Meanwhile, the phosphorylation of Akt, mTOR, and p70S6K were promoted, but that of 4EBP1 was suppressed. In vivo, the results of apoptosis, expression of CVB3 and pro-apoptosis factors, and phosphorylation of Akt/mTOR factors of CVB3-infected cardiomyocytes were consistent with that of vitro. Following that, we use Rapamycin and MK-2206 to inhibit the Akt/mTOR signaling pathway, meanwhile, Rattus 4EBP1, p70S6K, Akt1 and Akt2 were transfected to H9C2 cells to establish the stably transfected cell lines. In the group with Rapamycin or MK-2206 pretreatment, CPCs-Ex also could decrease the apoptosis of H9C2 cells and expression of CVB3 mRNA, followed by decreased expression of apoptosis factors. In Akt2, p70S6K and 4EBP1 overexpression groups, CPCs-Ex promoted CVB3-induced apoptosis, VP1 expression and cleavage of caspase-3. Our results therefore identify CPCs-Ex exerts an anti-apoptosis effect in CVB3-infected cells by abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways as well as the expression of Bcl-2 and caspase families. Viral myocarditis, mainly caused by CVB3 infection, is lacking a specific treatment. Our study identified an anti-apoptosis role of CPCs-Ex in CVB3-infected cells and rats, which shown that CPCs-Ex may be an effective tool to treat viral myocarditis. We believe that with more in-depth research on the functionality of CPCs-Ex, there will be a breakthrough in the treatment of viral myocarditis.

Highlights

Viral myocarditis (VMC) is a common cause of dilated cardiomyopathy and sudden cardiac death[1]
Compared with the lymphocyte lysates, samples have been demonstrated to contain a large number of exosomes, revealed that the tetraspanin molecule CD63 and CD81 were abundant in cardiac progenitor cells (CPCs)-Ex (Fig. 1d)
Years of research have confirmed that the role of CPCs in the repair of the heart is mainly through the paracrine, rather than directly differentiate into cardiomyocytes[6,26]

Summary

Introduction

Viral myocarditis (VMC) is a common cause of dilated cardiomyopathy and sudden cardiac death[1]. Finding effective therapies for VMC is still a big challenge, CPCs are a group of heterogeneous cells distributed throughout the heart and able to differentiate into several cell types, such as cardiomyocytes (CMs), vascular smooth muscle cells and endothelial cells (ECs), holding great promise for cardiac regeneration and functional reconstruction. Stem-cell therapy has yielded encouraging results in heart repair[3,4,5]. Li et al Cell Death and Disease (2019)10:691 candidates for cardiac cell therapy compared with stem cells from bone marrow or adipose tissue[6]. The mechanism of adult stem-cell therapy has been tested to be mediated through paracrine release of extracellular vesicles containing growth factors and cytokines to exert anti-apoptosis, suppress immunity, and promote angiogenesis[6,7]. Exosomes may be the major active components of extracellular vesicles derived from CPCs8

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