HLA‐E^high/HLA‐G^high/HLA‐II^low Human iPSC‐Derived Cardiomyocytes Exhibit Low Immunogenicity for Heart Regeneration

Abstract

Although human induced pluripotent stem cells (hiPSCs)‐derived cardiomyocytes (hiPSC‐CMs) can remuscularize infarcted hearts and restore post‐infarct cardiac function, post‐transplant rejection resulting from human leukocyte antigen (HLA) mismatching is an enormous obstacle of cell therapy. Therefore, it is crucial to identify hypoimmunogenic hiPSCs for allogeneic cell therapy. We conducted this study to demonstrate the immune privilege of HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐derived cardiomyocytes (hiPSC‐CMs) in vitro. Then we did ischemia‐reperfusion surgery to create transmural myocardial infarction in rats. At post‐infarct 4 days, we injected hPSC‐CMs (1.0×107 cells/kg), including human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs), hiPSC‐CMs and HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs, into the infarcted myocardium. Compared with hESC‐CMs and hiPSC‐CMs, under the treatment of very low dose cyclosporine A (CsA), only HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CM survived in vivo, remuscularized the infarcted myocardium with infarct size reduction and improved post‐infarct cardiac function. HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs evaded attack by natural killer (NK) cells and cytotoxic T cells because these hiPSC‐CMs activated the SHP‐1 signaling pathway of NK cells and cytotoxic T cells which downregulated STAT‐1 and NF‐κB expression. Herein, we demonstrated that using clinically relevant CsA dose, HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSC‐CMs repaired the infarcted myocardium and restored the post‐infarct heart function. HLA‐Ehigh/HLA‐Ghigh/HLA‐IIlow hiPSCs are less immunogenic and may serve as platforms for regeneration medicine.This article is protected by copyright. All rights reserved

Noninvasive Assessment of hiPSC Differentiation toward Cardiomyocytes Using Pretrained Convolutional Neural Networks and the Channel Pruning Algorithm

“…4 HiPSC-derived cardiomyocytes (hiPSC-CMs), free from ethical concerns associated with embryonic stem cells, possess the structural, regulatory, and functional attributes of human cardiomyocytes, making them valuable in precision medicine, 5,6 drug screening, 3,7 and cardiac tissue engineering. 8,9 To meet the growing demand for these cells for various applications, automatic hiPSC culture and differentiation systems have been developed and made commercially available. 10,11 Moreover, the diverse and high-throughput applications of hiPSC-CMs typically rely on the success and efficient differentiation of hiPSCs toward cardiomyocytes.…”

“…Human induced pluripotent stem cells (hiPSCs) have an intrinsic capability for indefinite self-renewal and differentiation into various types of cells, including cardiomyocytes . HiPSC-derived cardiomyocytes (hiPSC-CMs), free from ethical concerns associated with embryonic stem cells, possess the structural, regulatory, and functional attributes of human cardiomyocytes, making them valuable in precision medicine, , drug screening, , and cardiac tissue engineering. , …”