BACKGROUND Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. OBJECTIVES The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model. METHODS Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 107 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas. RESULTS Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4 weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group. CONCLUSIONS Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4 weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.

中文翻译：

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人源性多能干细胞衍生的心肌细胞的移植改善了梗塞大鼠心脏的心肌功能并逆转了心室重构。

背景技术人源性多能干细胞衍生的心肌细胞（iPSC-CM）对心脏再生医学尤其是对心力衰竭患者的心肌修复提供了很大的启发。但是，iPSC-CMs在移植后的体内治疗效果和存活率均不一致。目的本研究的目的是评估人iPSC-CM在大鼠梗死后心力衰竭模型中改善心肌功能的能力。方法随机选择8周龄雄性Sprague-Dawley大鼠，在进行左前降支（LAD）结扎冠状动脉结扎10天后，接受5％的白蛋白溶液心肌内注射，含或不含1×107个人iPSC-CM。在注射iPSC-CM之前，先给予环孢菌素A和甲基泼尼松龙，直到杀死大鼠以防止移植排斥。通过超声心动图评估心脏功能。通过观察荧光细胞示踪剂Vybrant™CM-DiI或移植的细胞中增强的绿色荧光蛋白（eGFP）的表达来确认移植的心肌细胞的存活，或通过基于聚合酶链反应（PCR）的人类线粒体检测证明存活脱氧核糖核酸。天狼星红染色用于评估纤维化率。用苏木精-伊红染色观察畸胎瘤的形成。结果心肌内注射iPSC-CMs后四周，进行iPSC-CM移植的动物死亡率低于对照组。注射无细胞溶液的动物（对照组）表现出明显的左心室（LV）功能退化，而移植iPSC-CM则减弱了这种重塑过程。在对照组中，射血分数恶化了10.11％（从46.36降低到41.67％），而分数缩短则恶化了9.23％（从24.37降低到22.12％），持续了4周。在iPSC-CM注射组中，射血分数提高了18.86％（从44.09增至52.41％），而缩短分数提高了23.69％（从23.08增至28.54％）。细胞标记，追踪和分子生物学技术表明，iPSC-CM移植后1个月，移植的心肌细胞在大鼠心脏中存活。iPSC-CM治疗组的心肌纤维化也有所减轻。结论人iPSC-CM移植物在梗死的大鼠心脏中存活，并在移植后4周恢复了心肌功能。细胞替代疗法还可以逆转心室重构，表明iPSC-CM在心脏修复策略中的潜力。