Background. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are under preclinical investigation as a cell-based therapy for heart failure post-myocardial infarction. In a previous study, tissue-engineered cardiac grafts were found to improve hosts’ cardiac electrical and mechanical functions. However, the durability of effect, immune response, and in vitro properties of the tissue graft remained uncharacterized. This present study is aimed at confirming the graft therapeutic efficacy in an immune-competent chronic heart failure (CHF) model and providing evaluation of the in vitro properties of the tissue graft. Methods. hiPSC-CMs and human dermal fibroblasts were cultured into a synthetic bioabsorbable scaffold. The engineered grafts underwent epicardial implantation in infarcted immune-competent male Sprague-Dawley rats. Plasma samples were collected throughout the study to quantify antibody titers. At the study endpoint, all cohorts underwent echocardiographic, hemodynamic, electrophysiologic, and histopathologic assessments. Results. The epicardially placed tissue graft therapy improved () in vivo and ex vivo cardiac function compared to the untreated CHF cohort. Total IgM and IgG increased for both the untreated and graft-treated CHF cohorts. An immune response to the grafts was detected after seven days in graft-treated CHF rats only. In vitro, engineered grafts exhibited responsiveness to beta-adrenergic receptor agonism/antagonism and SERCA inhibition and elicited complex molecular profiles. Conclusions. This hiPSC-CM-derived cardiac graft improved systolic and diastolic cardiac function in immune-competent CHF rats. The improvements were detectable at seven weeks post-graft implantation despite an antibody response beginning at week one and peaking at week three. This suggests that non-integrating cell-based therapy delivered by a bioengineered tissue graft for ischemic cardiomyopathy is a viable treatment option.

中文翻译：

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心力衰竭免疫活性大鼠模型中的心外膜生物工程心肌细胞异种移植物

背景。人类诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 正在临床前研究中，作为心肌梗死后心力衰竭的细胞疗法。在之前的一项研究中，发现组织工程心脏移植物可以改善宿主的心脏电和机械功能。然而，组织移植物的效果、免疫反应和体外特性的持久性仍未确定。本研究旨在确认移植物在免疫功能正常的慢性心力衰竭 (CHF) 模型中的疗效，并评估组织移植物的体外特性。方法. hiPSC-CMs 和人真皮成纤维细胞被培养成合成的生物可吸收支架。工程移植物在梗塞免疫能力强的雄性 Sprague-Dawley 大鼠中进行心外膜植入。在整个研究过程中收集血浆样品以量化抗体滴度。在研究终点，所有队列都接受了超声心动图、血流动力学、电生理学和组织病理学评估。结果。心外膜组织移植治疗得到改善（) 与未治疗的 CHF 队列相比，体内和离体心脏功能。未治疗和移植物治疗的 CHF 队列的总 IgM 和 IgG 均增加。仅在接受移植物治疗的 CHF 大鼠 7 天后检测到对移植物的免疫反应。在体外，工程移植物表现出对 β-肾上腺素能受体激动/拮抗和 SERCA 抑制的反应，并引发了复杂的分子谱。结论. 这种 hiPSC-CM 衍生的心脏移植物改善了免疫能力强的 CHF 大鼠的收缩和舒张心脏功能。尽管抗体反应从第一周开始并在第三周达到峰值，但在移植后七周可以检测到这些改善。这表明通过生物工程组织移植物为缺血性心肌病提供的基于细胞的非整合疗法是一种可行的治疗选择。