Mesenchmal Stem Cells Driven By Exosomes Protect Against Myocardial Infarction Via P53-mediated Autophagy Signalling

Backround and Objective:Myocardial infarction is a major disease hazard to human health.The congestive heart failure is the main cause of death by myocardial infarction.How to promote the repair and functional reconstruction of the heart after myocardial infarction is a key scientific issue in the field of cardiovascular research.Studies have shown that bone marrow mesenchymal stem cells(MSCs)transplantation can make use through paracrine,reducing the infarct area of heart.Therefore it will increase the rate of myocardiocyte viability.Mesenchymal stem cells transplantation have ability of immunosuppressive properties.This way is an effective method to repair and functional reconstruction of myocardial tissue.However,the molecular biological mechanism has not been fully revealed.Autophagy is an evolutionarily conserved function of cells for the removal of their organelles and metabolic wastes.Autophagy plays an important role in various cardiovascular diseases.Autophagy plays an important role in cell survival.In the ischemia/reperfusion model,autophagy flux will increase at the stage of ischemia and enhanced autophagy now has a protective effect on the heart while excessive autophagy during the stage of reperfusion is harm to cardiac cells.In order to understand in-depth study of mesenchymal stem cell transplantation and the role of autophagy in cell therapy,we use MI model in mice to further clarify the mechanism of autophagy pathway in stem cells for treatment of myocardial infarction.Methods and results:In vivo,we established a mouse model of myocardial infarction and transplanted bone marrow mesenchymal stem cells(MSCs)into the myocardium after myocardial infarction.The changes of cardiac function and cardiac remodeling after 1,3,7,28 days of the mice were observed and compared with the changes of autophagy flux in the mouse heart tissue.We found that the transplantation of mesenchymal stem cells can reduce myocardial apoptosis and improve heart function after myocardial infarction.After myocardial infarction,the level of autophagy flux in cardiac tissue was increased while the level of autophagy in cardiac tissue was decreased after transplantation of mesenchymal stem cells.In vitro experiments,we co-cultured mesenchymal stem cells(MSCs)with neonatal mice cardiomyocytes.We mimic the condition of hypoxia in hypoxic incubator and detect the level of autophagy flux.We found that after 24 hours of hypoxia,the death rate of myocardial cells was increased and the level of autophagy flux was up-regulated while the death rate of myocardial cells was decreased and the level of autophagy flux was down-regulated after MSCs coculture.And cell death rate was reduced after the use of autophagy inhibitor.In hypoxia group,the level of p53 increased and the mitochondrial membrane potential decreased while in the co-culture group,the level of p53 decreased,and the mitochondrial membrane potential of myocardial cells was higher than that of hypoxia group.In order to further study what substances the mesenchymal stem cells secrete,and then regulate the level of autophagy flux in myocardial cells.We extracted the exosomes from the mesenchymal stem cells(MSCs),and found that there was the same phenomenon compared with the co-cultured group.In the exosome,mir-125b make an important role.Conclusion:In summary,mir-125b,mesenchymal stem cells can secreted,which affect the level of autophagy flux and decrease the death rate of myocardial cells after the MI through p53/bnip3 signaling pathway.It can reduce myocardial cell autophagic cell death,which can improve cardiac function and reduce cardiac remodeling.