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.
Highlights
Viral myocarditis (VMC) is an important cause of heart failure, arrhythmia and sudden death in young people, which is related to immune injure, autophagy and apoptosis induced by viral infection.[1,2] In the past decades, myocarditis patients had partial or full clinical recovery with conventional medical treatment, immunomodulatory therapy and immunosuppressive therapy, but those who did not be recovered might develop into dilated cardiomyopathy.[3-6]
We successfully isolated human umbilical cord mesenchymal stem cells and identified exosomes derived from Human umbilical cord MSCs (hucMSCs)
Our results showed that the administration of hucMSC-exosomes following coxsackievirus B3 (CVB3)-induced myocarditis significantly decreased myocardial pathological injury and proinflammatory cytokines as well as increased LV ejection fraction (LVEF) and LVFS
Summary
Viral myocarditis (VMC) is an important cause of heart failure, arrhythmia and sudden death in young people, which is related to immune injure, autophagy and apoptosis induced by viral infection.[1,2] In the past decades, myocarditis patients had partial or full clinical recovery with conventional medical treatment, immunomodulatory therapy and immunosuppressive therapy, but those who did not be recovered might develop into dilated cardiomyopathy.[3-6]. Mesenchymal stem cells (MSCs) derived from different tissues including bone marrow, adipose and umbilical cord are commonly used in tissue repair and regeneration.[7-9]. The transfusion of MSCs derived from bone marrow, adipose and umbilical cord showed therapeutic effects on type 2 diabetes rat models and even patients.[10-13]. The study had demonstrated that MSCs through paracrine pathway play a major role in tissue repair and regeneration.[20]. Timmers et al reported that myocardial ischaemia/reperfusion injury could be repaired by factors with molecular weight greater than 1000 kD in human embryonic MSC medium, and they further confirmed these factors were exosomes derived from MSCs.[23]. In this study, we will investigate whether hucMSC-exosomes can play a protective role in the coxsackievirus B3 (CVB3)-induced myocarditis and explore the underlying mechanisms
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