Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
Stem Cell Res Ther. 2024 Mar 13;15(1):73. doi: 10.1186/s13287-024-03690-8.
Cell- or tissue-based regenerative therapy is an attractive approach to treat heart failure. A tissue patch that can safely and effectively repair damaged heart muscle would greatly improve outcomes for patients with heart failure. In this study, we conducted a preclinical proof-of-concept analysis of the efficacy and safety of clinical-grade human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches.
A clinical-grade hiPSC line was established using peripheral blood mononuclear cells from a healthy volunteer that was homozygous for human leukocyte antigens. The hiPSCs were differentiated into cardiomyocytes. The obtained hiPSC-CMs were cultured on temperature-responsive culture dishes for patch fabrication. The cellular characteristics, safety, and efficacy of hiPSCs, hiPSC-CMs, and hiPSC-CM patches were analyzed.
The hiPSC-CMs expressed cardiomyocyte-specific genes and proteins, and electrophysiological analyses revealed that hiPSC-CMs exhibit similar properties to human primary myocardial cells. In vitro and in vivo safety studies indicated that tumorigenic cells were absent. Moreover, whole-genome and exome sequencing revealed no genomic mutations. General toxicity tests also showed no adverse events posttransplantation. A porcine model of myocardial infarction demonstrated significantly improved cardiac function and angiogenesis in response to cytokine secretion from hiPSC-CM patches. No lethal arrhythmias were observed.
hiPSC-CM patches are promising for future translational research and may have clinical application potential for the treatment of heart failure.
基于细胞或组织的再生治疗是治疗心力衰竭的一种有吸引力的方法。一种能够安全有效地修复受损心肌的组织贴片将极大地改善心力衰竭患者的预后。在这项研究中，我们对临床级人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）贴片的疗效和安全性进行了临床前概念验证分析。
使用来自健康志愿者的外周血单核细胞建立了临床级 hiPSC 系，该志愿者为人类白细胞抗原纯合子。将 hiPSC 分化为心肌细胞。获得的 hiPSC-CMs 在温度响应培养皿上进行培养，以制备贴片。分析 hiPSC、hiPSC-CMs 和 hiPSC-CM 贴片的细胞特征、安全性和疗效。
hiPSC-CMs 表达心肌细胞特异性基因和蛋白质，电生理分析表明 hiPSC-CMs 具有与人原代心肌细胞相似的特性。体外和体内安全性研究表明不存在致瘤细胞。此外，全基因组和外显子组测序未发现基因组突变。一般毒性试验也显示移植后无不良事件。心肌梗死的猪模型显示，hiPSC-CM 贴片通过细胞因子分泌显著改善心脏功能和血管生成，没有致命性心律失常。
hiPSC-CM 贴片具有广阔的转化研究前景，可能具有治疗心力衰竭的临床应用潜力。
