Human induced pluripotent stem cell-derived cardiomyocytes improve recovery from myocardial infarction in non-human primates.

BACKGROUND: The transplantation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represents a promising next-generation cell therapy for repairing injured myocardium. However, the safety, efficacy, and pharmacokinetics of these cells in non-human primates (NHPs) with myocardial infarction (MI) have not been systematically investigated. METHODS: Sixteen rhesus monkeys underwent MI surgery, with 10 monkeys receiving 1 × 10(8) hiPSC-CMs through intramyocardial injection and six monkeys receiving vehicle alone. Echocardiography and cardiac MRI were performed to evaluate the cardiac function and infarct size. A wearable electrocardiogram monitoring device was used to detect postoperative arrhythmias. The bio-distribution of grafted cells in a separate cohort of four monkeys was explored via positron emission tomography/computed tomography (PET/CT) tracking using zirconium 89 ((89)Zr)-prelabeled hiPSC-CMs. Quantitative real-time polymerase chain reaction and immunostaining were used to detect the grafted cells in the host. RESULTS: hiPSC-CM transplantation significantly improved cardiac performance at 4 and 12 weeks after MI, including left ventricular (LV) ejection fraction, fractional shortening, end-systolic volume, and internal dimension at end-systole. Furthermore, cell transplantation reduced myocardial infarct size, reversed cardiac hypertrophy, and increased angiogenesis 12 weeks after MI. Although there was a higher incidence of arrhythmias in the cell therapy group compared to the control group, it was resolved 2 weeks after cell transplantation. The survival of multiple islands of human myocardial cells in the host hearts was identified 12 weeks after cell implantation, indicating the remuscularization potential of hiPSC-CMs. Consistent with this, PET/CT tracking of (89)Zr-prelabeled hiPSC-CMs showed a high retention of the radioactivity in the heart 2 weeks after transplantation. Additionally, the human mitochondrial DNA assay revealed that, except for the heart, no evidence of human cells was observed in the other organs after injection. CONCLUSIONS: The transplantation of hiPSC-CMs can effectively repair injured cardiac tissue in an NHP MI model without any adverse off-target effects. Therefore, the direct intramyocardial injection of hiPSC-CMs is a promising, effective, and safe strategy for treating MI.