Transplantation Of Trophoblast Stem Cells For Cardiac Regeneration After Myocardial Infarction

Background and objective:Myocardial infarction leads to massive loss of cardiomyocytes,the renewal of existing cardiomyocytes is unable to repair the necrotic tissue.In the past few years,the use of stem cell therapy for myocardial infarction has been reported to heal the impaired myocardium and improve cardiac function,however,the new treatment was limited by ethical controversy,teratoma formation,immune response,and the poor differentiation into cardiomyocytes.Until now,an ideal candidate has not been found.Recently,Kara et al study found that fetal cells expressed Caudal-related homeobox2(Cdx2)could home to the site of injury after murine maternal myocardial infarction and differentiate into cardiomyocytes,endothelial cells,and these cells appear to be capable of differentiating into beating cardiomyocytes in vitro.Cdx2 is a marker of trophoblast stem cells(TSCs),the previous research suggested that TSCs may be a novel cell type for cardiac regeneration.Here,our objective is to evaluate the feasibility of TSCs in transplantation for myocardium regeneration after myocardial infarction.Methods:We isolated and cultured trophoblast stem cells(TSCs)and bone marrow-derived mesenchymal stem cells(MSCs)from C57BL/6-eGFP mice.Wild-type C57BL/6 male mice were subjected to coronary ligation of acute myocardial infarction(AMI),then we transplanted 5×105 GFPTSCs(n=20),5×105 GFP-MSCs(n=20)and PBS(n=14)into the infarction area and border zone of myocardium through intramyocardial injection.The cardiac function were evaluated by echocardiography at 2week and 3week after transplantation.After 3weeks,the hearts were harvested and performed the histopathological analysis,the differentiation,infarct size,cardiac fibrosis,capillary density,cell apoptosis and proliferation were measured.The potential paracrine effects of TSCs were assessed using microarray.Results:The mice received TSCs and MSCs exhibited increased LVEF(p<0.05)and FS(p<0.05)at 2week or 3week compared with PBS injection.The cells-injected groups also showed reduced scar size(p<0.05)and fibrosis(p<0.05).In addiation,cell therapy displayed increased angiogenesis,cell proliferation,and reduced cell apoptosis.In contrast with MSCs,more cell proliferation,especially cardiomyocytes proliferation were found in the border zone in TSCs-injected group.In vivo,stem cells were found within injured myocardium and boder zone,and we found that TSCs differentiate into cardiomyocytes,but rare.However,we did not observe this phenomenon in MSCs-injection grounp.The differentiation into endothelial cells was also detected in low numbers in two cell therapy grounp.Microarray analysis revealed that the benefit may be associated with the downregulation of miR-200b-3p after TSCs transplantation.Conclusion:Transplantation of TSCs after myocardial infarction lead to better cardiac function,this was mainly achieved through reduced infarcted size,fibrosis,apoptosis and increased angiogenesis,cell proliferation.Compared with MSCs,we did not observe advantages for the improvement of cardiac function,but TSCs may have more potential in promoting cell proliferation,especially cardiomyocytes,which is likely to be mediated by the downregulation of miR-200b-3p.The application of TSCs in myocardial injury repair remains to be studied further more.