Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 24, Issue 13, Pages 7515-7530Publisher
WILEY
DOI: 10.1111/jcmm.15378
Keywords
AMPK; apoptosis; exosomes; human umbilical cord mesenchymal stem cells; mTOR-mediated autophagy flux; viral myocarditis
Categories
Funding
- National Natural Science Foundation of China [81701426, 81970435, 81770502, 81870281]
- Natural Science Foundation of Zhejiang Province [LY20H040003, LY18H020011, LQ19H020005]
- Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China [2020ZX09201002]
- Major Medical and Health Science and Technology Plan of Zhejiang Province [WKJ-ZJ-1725]
- Medical and Health Research Science and Technology Plan Project of Zhejiang Province [2018KY523, 2017KY475]
- Public Welfare Science and Technology Plan Project of Wenzhou City [Y20180097, Y20190162]
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Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-exosomes) have been implicated as a novel therapeutic approach for tissue injury repair and regeneration, but the effects of hucMSC-exosomes on coxsackievirus B3 (CVB3)-induced myocarditis remain unknown. The object of the present study is to investigate whether hucMSC-exosomes have therapeutic effects on CVB3-induced myocarditis (VMC). HucMSC-exosomes were identified using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. The purified hucMSC-exosomes tagged with PKH26 were tail intravenously injected into VMC model mice in vivo and used to administrate CVB3-infected human cardiomyocytes (HCMs) in vitro, respectively. The effects of hucMSC-exosomes on myocardial pathology injury, proinflammatory cytokines and cardiac function were evaluated through haematoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) and Doppler echocardiography. The anti-apoptosis role and potential mechanism of hucMSC-exosomes were explored using TUNEL staining, flow cytometry, immunohistochemistry, Ad-mRFP-GFP-LC3 transduction and Western blot. In vivo results showed that hucMSC-exosomes (50 mu g iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC-exosomes (50 mu g/mL) inhibited the apoptosis of CVB3-infected HCM through increasing pAMPK/AMPK ratio and up-regulating autophagy proteins LC3II/I, BECLIN-1 and anti-apoptosis protein BCL-2 as well as decreasing pmTOR/mTOR ratio, promoting the degradation of autophagy flux protein P62 and down-regulating apoptosis protein BAX. In conclusion, hucMSC-exosomes could alleviate CVB3-induced myocarditis via activating AMPK/mTOR-mediated autophagy flux pathway to attenuate cardiomyocyte apoptosis, which will be benefit for MSC-exosome therapy of myocarditis in the future.
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