BACKGROUND:The clinical application of human induced pluripotent stem cell–derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell–derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell–derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts.METHODS:We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell–derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×10⁷ CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×10⁷ CMs).RESULTS:Recipients of hiPSC-CSs containing 2×10⁷ CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×10⁷ CMs.CONCLUSIONS:We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products.

中文翻译：

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利用人类诱导多能干细胞来源的心脏球体再生非人类灵长类动物心脏

背景：人类诱导多能干细胞来源的心肌细胞（CM）用于心脏修复的临床应用始于工程心脏组织的心外膜递送；然而，由于担心 CM 植入不良和移植后心律失常，将人类诱导多能干细胞衍生的 CM 直接递送至心肌层（据报道可诱导电整合）的可行性尚不清楚。因此，在本研究中，我们制备了纯化的人诱导多能干细胞来源的心脏球体（hiPSC-CS），并研究了直接注射它们是否可以再生梗塞的非人灵长类动物心脏。 方法：我们进行了 2 个单独的实验来探索适当数量的人类心脏球体诱导多能干细胞衍生的 CM。在第一个实验中，10只食蟹猴在移植前2周发生心肌梗塞，并被指定为含有2×10 ⁷ CM的hiPSC-CS或载体的受体。移植后12周对动物进行安乐死进行组织学分析，并在观察期间监测心功能和心律失常。在第二项研究中，我们使用更多的 CM（6×10 ⁷ CM）重复了等效的移植研究。 结果：与接受者相比，含有 2×10 ⁷ CM的 hiPSC-CS 的接受者表现出有限的 CM 移植和短暂的缩短分数增加。载体（移植后4周缩短分数：26.2±2.1%；19.3±1.8%；P <0.05），移植后心律失常发生率低。移植增加剂量的 CM 导致显着更大的植入和长期收缩益处（移植后 12 周的缩短分数：22.5±1.0%；16.6±1.1%；P <0.01，移植后 12 周的左心室射血分数： 49.0±1.4%；36.3±2.9%；P <0.01)。含有 6×10 ⁷ CM的 hiPSC-CS 受体中，移植后心律失常的发生率略有增加。结论：我们证明，直接注射 hiPSC-CS 可以恢复受损灵长类动物心脏的收缩功能，且移植后心律失常的风险可接受。尽管功能益处的机制尚未完全阐明，但这些发现为使用等效 CM 产品进行临床试验提供了强有力的理由。