Therapeutic Effect Of Human Embryonic Stem Cell-derived Cardiovascular Progenitor Cells In Infarcted Nonhuman Primates

Background and Objective:Human pluri potent stem cell-derived cardiovascular progenitor cells(hPSC-CVPCs)should be thoroughly investigated in large animal studies before testing in clinical trials.To clarify if hPSC-CVPCs can engraft for long time in the heart of primates after myocardial infarction(Ml)and compare the effectiveness and safety of immunosuppression with cyclosporine alone or multiple-drug regimen(MDR)containing cyclosporine,methylprednisolone,and Simulect in cynomolgous monkeys that had received intramyocardial injections of 1×107 EGFP-expressing hPSC-CVPCs after MI.A third group of animals received the immunosuppression MDR but without cell therapy after MI(MI+MDR group).Methods and Results:Measurements of EGFP gene levels and EGFP immunofluorescence staining indicated that the hPSC-CVPC engraftment rate was greater in the MI+MDR+CVPC group than that in the MI+Cyclosporine+CVPC group.However,even in the MI+MDR+CVPC group,no transplanted cells could be detected at 140 days after transplantation.Concomitantly,irnunofluorescent analysis of CD3,CD4,and CD8 expression indicated that T lymphocyte infiltration in the CVPC-transplanted hearts was less in the MDR-treated animals than in the cyclosporine alone-treated animals.The recovery of left-ventricular(LV)function at day 28 post-MI in the MI+MDR+CVPC group was better than that in the MI+MDR group.Apoptotic cardiac cells were also less common in the MI+MDR+CVPC group than in the MI+MDR group,while both immunosuppression regimens were associated with transient hepatic dysfunction.Conclusions:This is the largest study of hPSCs in non-human primates in cardiovascular field so far(n=32).Compared to cyclosporine alone,MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates;this is associated with less apoptosis of native cardiac cells and better recovery of LV function at 28 days.However,even with MDR,transplanted hPSC-CVPCs do not engraft and do not survive at 140 days after transplantation,thereby excluding remuscularization as a mechanism for the functional effect.