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

  • J Cell Mol Med. 2020 Jul;24(13):7515-7530. doi: 10.1111/jcmm.15378.
Xiaohong Gu  1 ,  Yuechun Li  1 ,  Kaixin Chen  1 ,  Xingang Wang  1 ,  Zhongyu Wang  1 ,  Hao Lian  1 ,  Yuanzheng Lin  1 ,  Xing Rong  1 ,  Maoping Chu  1  2 ,  Jiafeng Lin  1 ,  Xiaoling Guo  1  2
Affiliations
  • 1. Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2. Center of Scientific Research, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
PMID: 32424968 DOI: 10.1111/jcmm.15378
Abstract

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 μg iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC-exosomes (50 μg/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.

Keywords
AMPK; apoptosis; exosomes; human umbilical cord mesenchymal stem cells; mTOR-mediated autophagy flux; viral myocarditis.
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