Abstract GS102: Injection Of Human IPSC-derived Cardiac Cells Promote Cardiac Repair After Infarction In Nonhuman Primates

Abstract

Introduction: Injection of induced pluripotent stem cell-derived cardiomyocytes has been reported as a promising approach to regenerate loss myocardium and restore heart function after ischemic injury. However, immaturity of the transplanted cardiomyocytes and their poor survival rates caused by limited blood supply remain as major hurdles for clinical translation. Hypothesis: We tested the hypothesis that co-culture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) with hiPSC-derived endothelial cells (ECs) promotes CM maturation in vitro, and that co-transplantation of both hiPSC-CMs and hiPSC-ECs facilitates hiPSC-CM muscularization in myocardial ischemic injured mice and non-human primates. Methods and Results: We examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in NOD-SCID mice undergoing myocardial infarction (N = 14 / group). Mice receiving co-transplantation had an improvement in ejection fraction compared to control (4.2 ± 1.2 % vs -8.4 ± 0.9 %, P < 0.0001), and even those receiving high-dose (-0.3 ± 0.9 %, P = 0.052) and low-dose (-2.4 ± 1.1 %, P = 0.001) hiPSC-CMs alone treatment. Moreover, less arrhythmic events were observed in co-transplantation using three-lead electrogram. To be more clinically relevant, we first showed in healthy non-human primates (N = 4) that hiPSC-CM engraftment, maturation, and integration was achieved when co-transplanted with hiPSC-ECs. Furthermore, we then examined the therapeutic effect of co-transplantation of hiPSC-CMs and hiPSC-ECs in rhesus macaques undergoing ischemia-reperfusion surgery (N = 3 / group). Consistent with the mouse model, co-transplantation in rhesus macaques significantly improved the ejection fraction (10 ± 1.3 % vs -1.8 ± 2.2 %, P = 0.010), accompanied by a reduced infarct size compared to control (16 ± 1.1 % vs 23 ± 3.3 %, P = 0.091). Conclusions: This study demonstrates the beneficial effects of co-transplantation of hiPSC-CMs with hiPSC-ECs, promoting hiPSC-CM maturation, enhancing neovascularization, and improving cardiac function in both mouse and non-human primate hearts. Delivery of this combined cell therapy holds promise for future clinical translation.

Human iPSC-derived Committed Cardiac Progenitors Generate Cardiac Tissue Grafts in a Swine Ischemic Cardiomyopathy Model without Triggering Ventricular Arrhythmias

“…Even a combination of cell products may be preferable such as hiPSC-derived endothelial cells and hiPSC-CMs to promote cell survival and revascularization. 41 Ground breaking phase 1 clinical trials are testing hPSC-CMs to treat heart failure employing epicardial injections, 42 transcatheter injections (NCT04982081) and epicardial patches (NCT04945018, NCT04396899) are underway world-wide as well as a completed trial demonstrating the safety of hESC-SSEA1 + progenitor cells transplanted at the time of coronary artery bypass grafting surgery. 15 Despite these developments, important unanswered questions remain including concerns about immunogenicity, repeat dosing possibilities, electromechanical integration, arrhythmogenicity, and whether minimally invasive transcatheter administration will be feasible for wider adoption of this therapy.…”

“…Even a combination of cell products may be preferable such as hiPSC-derived endothelial cells and hiPSC-CMs to promote cell survival and revascularization. 41 Ground breaking phase 1 clinical trials are testing hPSC-CMs to treat heart failure employing epicardial injections, 42 transcatheter injections (NCT04982081) and epicardial patches (NCT04945018, NCT04396899) are underway world-wide as well as a completed trial demonstrating the safety of hESC-SSEA1 + progenitor cells transplanted at the time of coronary artery bypass grafting surgery. 15…”