Exosomes derived from umbilical cord mesenchymal stem cells alleviate viral myocarditis through activating AMPK/mTOR-mediated autophagy flux pathway

被引：106

作者：

Gu, Xiaohong ^{[1
,2
]}

Li, Yuechun ^{[1
,2
]}

Chen, Kaixin ^{[1
,2
]}

Wang, Xingang ^{[1
,2
]}

Wang, Zhongyu ^{[1
,2
]}

Lian, Hao ^{[1
,2
]}

Lin, Yuanzheng ^{[1
,2
]}

Rong, Xing ^{[1
,2
]}

Chu, Maoping ^{[1
,2
,3
]}

Lin, Jiafeng ^{[1
,2
]}

Guo, Xiaoling ^{[1
,2
,3
]}

机构：

[1] Wenzhou Med Univ, Affiliated Hosp 2, Inst Cardiovasc Dev & Translat Med, Wenzhou, Peoples R China

[2] Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou, Peoples R China

[3] Wenzhou Med Univ, Affiliated Hosp 2, Ctr Sci Res, Wenzhou, Peoples R China

来源：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE | 2020年 / 24卷 / 13期

基金：

中国国家自然科学基金;

关键词：

AMPK; apoptosis; exosomes; human umbilical cord mesenchymal stem cells; mTOR-mediated autophagy flux; viral myocarditis; EXTRACELLULAR VESICLES; PORCINE MODEL; HYPERGLYCEMIA; DIAGNOSIS; THERAPY; INJURY; PROTECT;

D O I：

10.1111/jcmm.15378

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：7515 / 7530

页数：16

共 65 条

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