Background: Stem cells are known to restore the injured myocardium. This capability may improve if there is enhanced in vivo survival of the transplanted stem cells. The hAMSCs are isolated from amniotic membrane underlying the chorion of a human placenta and are located in the fetal-maternal border, demonstrating unique immunomodulatory properties characterized by CD59 +, HLA-G +, and HLA-DR- to suppress the host immune response. A single polycistronic lentivirus reprograms the hAMSCs robustly to generate MiPSCs. Hypothesis: The MiPSCs retain the immunomodulatory properties of hAMSCs to attenuate immune rejection in an immunocompetent mouse to restore the injured myocardium. Methods and results: 250K MiPSCs were transplanted into the LAD ligated heart of FVB mice. 250K hAMSCs were injected into the hearts of LAD ligated immunodeficient SCID mice as control. In vivo bioluminescence (BLI) demonstrated robust viability signal in the luciferase-transduced MiPSCs for 2 weeks in FVB mice (Figure 1). When comparing the MiPSC-treated vs. the control (hAMSC-treated) mice during the 4-wk follow-up period, cardiac MRI demonstrated significantly improved LVEF (29.75 vs. 22.45%, p<0.05), decreased infarct % (21.47 vs. 31.06%, p<0.05), and increased viable myocardial volume (78.07 vs. 67.9 cm3, p<0.05). Notably, the MiPSCs did not form any teratoma. Conclusion: The MiPSCs exhibit unique immunomodulatory properties, which attenuate rejection by an immunocompetent mouse and significantly restore the injured heart. The MiPSCs may enable allogeneic cardiac stem cell therapy.