Cell therapy with human iPSC-derived cardiomyocyte aggregates leads to efficient engraftment and functional recovery after myocardial infarction in non-human primates

Abstract

AbstractBackgroundFunctionally coupled large myocardial grafts and a remarkable improvement of heart function in nonhuman primate models of myocardial infarction have been reported after transplantation of human embryonic stem cell-derived cardiomyocytes at relatively high numbers of up to 109single cell cardiomyocytes - a dose equivalent to total cell loss after myocardial infarction in ∼10 times larger human hearts. To overcome apparent limitations associated with the application of single cells, this pre-clinical study investigated the injection of cardiomyocyte aggregates instead.MethodsHuman iPSC-derived cardiomyocyte aggregates were produced in scalable suspension culture. Intramyocardial injection of the aggregates into cynomolgus monkey hearts was conducted two weeks after myocardial infarction induced by permanent coronary artery ligation. Human cell engraftment was assessed after two weeks or three months; functional analyses included continuous telemetric ECG recording and repeated cardiac MRI assessment in comparison to sham treated animals.ResultsTreatment with cell numbers as low as 5 x 107resulted in efficient structural engraftment. Notably, the degree of heart function recoveryin vivoseemed to correlate with the contractility of the applied cardiomyocytes tested by parallel experimentsin vitro. Graft-induced non-life-threatening arrhythmias were transient and decreased considerably during the three months follow-up.ConclusionsTransplantation of human iPSC-derived cardiomyocyte aggregates yielded comparable results to the reported application of higher numbers of single cell cardiomyocytes from human ESC, suggesting that the application of cardiomyocyte aggregates facilitates cell therapy development by reducing cell production costs and clinical risks associated with the administration of relatively high cell numbers.Clinical PerspectiveWhat is new?In contrast to previously applied single cells, human iPSC-derived cardiomyocyte aggregates (hiCMAs) were transplanted in a non-human primate (NHP) model of MI, to reduce the required cell dose, promote myocardial retention of the graft, and limit the risks for adverse effects. Such low-dose treatment with almost pure ventricular cardiomyocytes produced under GMP-compliant conditions, resulted in the formation of relative large, structurally integrated human grafts in NHP hearts.Transient non-life-threatening arrhythmias associated with intramyocardial cell transplantation decreased considerably during the three months follow-up.A remarkable recovery of left ventricular function was observed. This recovery notably correlated with thein vitrocontractility of transplanted cardiomyocyte batches tested in bioartificial cardiac tissues (BCTs), underlining the relevance of a suitable potency assay.What are the clinical implications?Intra-myocardial injection of hiCMAs is a promising treatment modality for the recovery of contractile function after MI; their advanced production, storage and testing revealed in the study facilitate the clinical translation of hiPSC-based heart repair.The need for relatively low numbers of cardiomyocytes produced through advanced protocols for scalable suspension culture reduces production costs of adequate cell batches, thereby increasing treatment availability.In vitrotesting of the produced cell batches is required to ensure treatment efficacy.Clinical hiCMA injection can be considered reasonably safe, however, pharmacological prevention and treatment of arrhythmias is required and temporary implantation of a cardioverter-defibrillator (ICD) could be considered.