The Role Of Mouse Bone Marrow MSC Exosomes With The Modulation Of Cardiac Inflammation In Doxorubicin-induced Dilated Cardiomyopathy

Aim:Dilated cardiomyopathy(DCM)is a common clinical manifestation of myocardial inflammation and a major cause of non-ischemic heart failure under 40 years old.DCM is characterized by ventricular enlargement,systolic dysfunction and is usually progressively aggravated.Many studies have shown that myocardial inflammation is the main initial link and risk factor of DCM,Macrophages as an important immune response cell play an important role in myocardial inflammation.Recent research studies have showed that mesenchymal stem cell(MSC)-derived exosomes have various functions in regulating inflammation,alleviating apoptosis and relieving cardiac remodeling after heart disease.Here we investigated the role of bone marrow MSC-derived exosomes in the development of inflammatory cardiomyopathy through regulating the activity of macrophages to improve the microenvironment of myocardial inflammationMethods:Exosomes were collected from the supernatants of conditioned media which is cultivated murine bone marrow mesenchymal stem cell and isolated by ultracentrifugation method.The 8 weeks old C57BL6 mice were subjected to an intraperitoneal injection of DOX(Doxorubicin)to induce model for dilated cardiomyopathy.After modeling,the mice received tail vein injection of either MSC-derived exosomes or PBS as control.Cardiac function changes in mice were monitored by echocardiography Four weeks later,cardiac tissues of mice were harvested for morphological examination and biochemical analysis to evaluate the effects of exosomes.Flow cytometry and immunohistochemistry were used to detect the changes of macrophage activation and infiltration in myocardium.Furthermore,changes in inflammatory signaling pathways and apoptosis in myocardial tissue of mice were detected by immunoblotting.Primary myocardial cells and myofibroblasts of neonatal mice were exposed by DOX or co-treatment with exosomes in vitro.Results:Mice receiving MSC-Exos showed improved cardiac function via echocardiography and attenuated cardiac dilation via HE staining,as well as reduced cardiomyocytes apoptosis.There was a significant decrease of the inflammatory cells infiltration in the MSC-Exos treatment group comparing to the PBS group.And the expression level of inflammatory factors were also reduced.Meanwhile,MSC-Exos could remarkly lower the pro-inflammatory macrophages amount in the DCM mice both blood and heart,which was proved that MSC-Exos relied on the JAK2-STAT6 pathway regulating macrophages activation.Conclusions:MSC-Exos improved the inflammatory microenvironment of dilated cardiomyopathy by regulating the polarization of the macrophage,which may hold promise for dilated cardiomyopathy clinical theraphy.