Feasibility, Safety, and Therapeutic Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheets in a Porcine Ischemic Cardiomyopathy Model
Feasibility, Safety, and Therapeutic Efficacy of Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Sheets in a Porcine Ischemic Cardiomyopathy Model
复制标题
DOI：
10.1161/circulationaha.111.084343
复制
发表时间：
2012-09-11
期刊：
影响因子：
37.8
通讯作者：
Sawa, Yoshiki
中科院分区：
文献类型：
--
作者：
Kawamura, Masashi;Miyagawa, Shigeru;Sawa, Yoshiki
背景-人诱导多能干细胞来源的心肌细胞（hiPS-CM）是用于再生心肌的有前途的细胞来源。然而，在hiPS细胞应用于临床之前，必须解决几个问题，特别是hiPS-CM的大规模制备和未分化iPS细胞的消除。细胞片层技术是移植大量细胞的有用方法之一。我们假设 hiPS-CM-sheet 移植对于治疗缺血性心肌病是可行、安全且有效的。方法和结果-通过用携带 Oct3/4、Sox2、Klf4 和 c-Myc 的逆转录病毒感染人真皮成纤维细胞来建立人 iPS 细胞。 WNT 信号分子诱导心肌分化，产生几乎 90% α-肌动蛋白、Nkx2.5 和心肌肌钙蛋白 T 阳性的 hiPS-CM。使用热敏培养皿创建 hiPS-CM 片，并将其移植到左前降支冠状动脉 Ameroid 收缩诱发的缺血性心肌病猪模型的心肌梗塞上（接受片移植的 iPS 组 n=6）和假手术组；两组均每天接受他克莫司）。移植显着改善了心脏功能并减弱了左心室重构。 hiPS-CM 在移植后 8 周即可检测到，但很少能长期存活。在接受hiPS-CM片的动物中未观察到畸胎瘤形成。结论-所使用的培养系统产生了大量高纯度的hiPS-CM，并且hiPS-CM片可以改善缺血性心肌病后的心功能。这种新开发的培养系统和hiPS-CM片可能为hiPS细胞在心脏再生治疗中的临床应用提供基础。 （流通。2012 年；S29-S37126[补充 1]：S29-S37。）
Background-Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are a promising source of cells for regenerating myocardium. However, several issues, especially the large-scale preparation of hiPS-CMs and elimination of undifferentiated iPS cells, must be resolved before hiPS cells can be used clinically. The cell-sheet technique is one of the useful methods for transplanting large numbers of cells. We hypothesized that hiPS-CM-sheet transplantation would be feasible, safe, and therapeutically effective for the treatment of ischemic cardiomyopathy.Methods and Results-Human iPS cells were established by infecting human dermal fibroblasts with a retrovirus carrying Oct3/4, Sox2, Klf4, and c-Myc. Cardiomyogenic differentiation was induced by WNT signaling molecules, yielding hiPS-CMs that were almost 90% positive for alpha-actinin, Nkx2.5, and cardiac troponin T. hiPS-CM sheets were created using thermoresponsive dishes and transplanted over the myocardial infarcts in a porcine model of ischemic cardiomyopathy induced by ameroid constriction of the left anterior descending coronary artery (n=6 for the iPS group receiving sheet transplantation and the sham-operated group; both groups received tacrolimus daily). Transplantation significantly improved cardiac performance and attenuated left ventricular remodeling. hiPS-CMs were detectable 8 weeks after transplantation, but very few survived long term. No teratoma formation was observed in animals that received hiPS-CM sheets.Conclusions-The culture system used yields a large number of highly pure hiPS-CMs, and hiPS-CM sheets could improve cardiac function after ischemic cardiomyopathy. This newly developed culture system and the hiPS-CM sheets may provide a basis for the clinical use of hiPS cells in cardiac regeneration therapy. (Circulation. 2012;S29-S37126[suppl 1]:S29-S37.)