In Vivo Differentiation of Induced Pluripotent Stem Cell-Derived Cardiomyocytes
In Vivo Differentiation of Induced Pluripotent Stem Cell-Derived Cardiomyocytes
复制标题
DOI：
10.1253/circj.cj-12-0977
复制
发表时间：
2013-05-01
影响因子：
3.3
通讯作者：
Matsuura, Nariaki
中科院分区：
文献类型：
--
作者：
Yu, Tao;Miyagawa, Shigeru;Matsuura, Nariaki
背景：诱导多能干细胞（iPSC）有望为治疗心力衰竭开辟一个新时代。然而，iPSC衍生的心肌细胞（iPSC-CM）的功能微观结构及其附着于受体心肌细胞外基质的能力需要进一步阐明。因此，我们分析了iPSC-CM的功能性微观结构和粘附分子。方法和结果：免疫染色分析显示，iPSC-CM在表达细胞骨架蛋白肌球蛋白重链（MHC）、肌球蛋白轻链（MLC）2a、MLC 2 v，尤其是β-MHC方面与新生心肌细胞（CM）相似（新生儿CM标志物），以及粘附分子N-钙粘蛋白、α 7-整联蛋白、肌营养不良蛋白、α-肌营养不良聚糖、α-肌聚糖和层粘连蛋白-α 2。电子显微镜显示，丰富的肌原纤维束与横向Z带和发达的线粒体结构在iPSC-CM和新生儿CM，虽然iPSC-CM含有较少的线粒体与低密度嵴。当从体外条件移植到裸鼠心脏时，iPSC-CM获得了表达α-MHC的能力，α-MHC是一种对成人CM特异性的分子。机械拉伸或胰岛素样生长因子-1刺激增强α-MHC表达iPSC-CMs在vitro.Conclusions：我们的研究结果在体外和体内表明，来自iPSC的CM包含心脏特异性细胞器和粘附系统。这些结果表明，iPSC衍生的CM可用于心力衰竭的新细胞疗法。(Circ J 2013; 77：1297-1306）
Background: Induced pluripotent stem cells (iPSCs) hold promise for a new era in treating heart failure. However, the functional microstructure of iPSC-derived cardiomyocytes (iPSC-CMs) and their ability to attach to the extracellular matrix of the recipient myocardium require further elucidation. Thus, we analyzed the functional microstructure and adhesion molecules of iPSC-CM.Methods and Results: Immunostaining analysis showed that iPSC-CMs were similar to neonatal cardiomyocytes (CMs) in expressing the cytoskeletal proteins myosin heavy chain (MHC), myosin light chain (MLC) 2a, MLC2v, and especially beta-mHC (a neonatal CM marker), as well as the adhesion molecules N-cadherin, alpha 7-integrin, dystrophin, alpha-dystroglycan, alpha-sarcoglycan, and laminin-alpha 2. Electron microscopy showed abundant myofibrillar bundles with transverse Z-bands and a developed mitochondrial structure in both iPSC-CMs and neonatal CMs, although the iPSC-CMs contained fewer mitochondria with lower-density cristae. When transplanted from in vitro conditions to nude rat hearts, iPSC-CMs acquired the ability to express alpha-MHC, a molecule specific to adult CMs. Mechanical stretch or stimulation by insulin-like growth factor-1 enhanced the alpha-MHC expression in iPSC-CMs in vitro.Conclusions: Our findings in vitro and in vivo indicate that CMs derived from iPSCs contain cardiac-specific organelles and adhesion systems. These results indicate that iPSC-derived CMs may be useful in new cell therapies for heart failure. (Circ J 2013; 77: 1297-1306)