Role Of Notch Signaling Pathway In The Treatment Of Dilated Cardiomyopathy With Umbilical Cord Mesenchymal Stem Cells

Objective To investigate the role of Notch signaling pathway in the treatment of dilated cardiomyopathy with human umbilical cord mesenchymal stem cells.Methods1.Therapeutic effect of human umbilical cord mesenchymal stem cells on γ-secretase inhibitor-induced dilated cardiomyopathy in Syrian golden hamsters60 male healthy Syrian golden hamster(referred to as hamster)were randomly divided into normal group(n = 15),experimental group(divided into DAPT group,DAPT control group and h HUCMSCs group,each 15).The hamsters in the experimental group were injected with γ-secretase inhibitor(DAPT),meanwhile,DAPT control group(DMEM group)and h HUCMSCs group were injected with the stem cell resuscitation medium DMEM and human umbilical cord mesenchymal stem cells(h HUCMSCs).The cardiac function of the hamsters was evaluated by echocardiography and plasma BNP.While myocardial tissue underwent HE and Masson staining.2.The activity of Notch signaling pathway in the treatment of dilated cardiomyopathy with umbilical cord mesenchymal stem cells110 SPF healthy and male SD rats were randomly divided into normal group(n = 20),dilated cardiomyopathy group(DCM group,n = 90).DCM rats were injected with 2mg /kg doxorubicin a week for 8 weeks to construct dilated cardiomyopathy model.60 successfully established DCM rats in DCM group were randomly divided into DCM control group(DMEM group,Intramuscular injection of 2ml DMEM),h HUC-MSCs low dose group(referred to as low dose group),h HUC-MSCs high dose group(referred to as high dose group).After 2 weeks and 4 weeks of h HUC-MSC treatment,cardiac function was assessed by echocardiography independently.The levels of plasma brain natriuretic peptide were measured by enzyme-linked immunosorbent assay.Western Blot was used to detect myocardial NICD(intracellular segment of Notch signaling pathway)and Hes1 protein content.Results1.Therapeutic effect of human umbilical cord mesenchymal stem cells on γ-secretase inhibitor-induced dilated cardiomyopathy in Syrian golden hamsters Before and after treatment the statistically difference of the echocardiographic results were not significant(P> 0.05).The difference between the DAPT group,the DMEM group and the normal group,h HUCMSCs group was statistically significant(P <0.01),but the stem cell group had no significant difference with the normal group(P> 0.05).The difference of the plasma BNP levels between the DAPT group,the DMEM group and the normal group,h HUCMSCs group were statistically significant(P <0.01),but the stem cell group had no significant difference with the normal group(P> 0.05).Compared with the DAPT group and the DMEM group,the myocardial cells in the normal group and the stem cell group were reduced,the inflammatory cell infiltration was reduced,and the myocardial fibers were arranged neatly.Masson staining showed decreased deposition of collagen fibers in the myocardium of the stem cells.2.The activity of Notch signaling pathway in the treatment of dilated cardiomyopathy with umbilical cord mesenchymal stem cells There was no significant difference in echocardiography in normal group before and after treatment for 2 weeks and 4 weeks.The results of echocardiography after h HUC-MSCs transplantation showed that the DMEM group,low dose group and high dose group were not statistically significant before and after treatment.The difference of LVEDD and LVESD between DMEM group,low dose group and high dose group was not statistically significant before and after treatment,however,LVEF and LVFS were significantly higher than those in DMEM group(P <0.05).Western Blot test results showed that there was no significant difference in NICD and Hes1 protein content between groups after 4weeks of treatment.Conclusion1.HUCMSCs can effectively improve the cardiac function of dilated cardiomyopathy in hamsters after the inhibition of Notch pathway.2.Notch signaling activity in myocardial tissue of doxorubicin-induced dilated cardiomyopathy rats was not significantly changed compared with of normal rats.Intermuscular infection of HUCMSCs improve cardic function of doxorubicin-induced dilated cardiomyopathy rats.However,it did not influence Notch signaling activity in cardic tissue signaificantly.These results suggest that the therapeutic effect of h UCMSCs on dilated cardiomyopathy does not rely on regulation of Notch signaling.