Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease1–6. However, the predictive power of these models is presently limited by the immature state of the cells1, 2, 5, 6. Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 µm) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force–frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease.A tissue culture system that provides an increasing intensity of electromechanical stimulation over time enables an in vitro model of cardiac tissue derived from human induced pluripotent stem cells to develop many of the characteristics of adult cardiac tissue.

中文翻译：

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从多能干细胞生长的人类心脏组织的高级成熟

由人类诱导的多能干细胞 (iPSC) 产生的心脏组织可以作为针对特定患者的生理学和疾病研究的平台1-6。然而，这些模型的预测能力目前受到细胞未成熟状态的限制1、2、5、6。在这里，我们表明，如果心脏组织在不久后由早期 iPSC 衍生的心肌细胞形成，则可以克服这一基本限制自发收缩的开始，并随着时间的推移受到强度增加的身体调节。仅培养 4 周后，对于研究的所有 iPSC 细胞系，这些组织都显示出类似成人的基因表达谱、组织有序的超微结构、生理肌节长度 (2.2 µm) 和线粒体密度 (30%)、横小管的存在、氧化代谢，正的力-频率关系和功能性钙处理。机电特性发展得更慢，没有达到成人心肌的成熟阶段。组织成熟是实现对异丙肾上腺素的生理反应和重现病理肥大所必需的，支持该组织模型在心脏发育和疾病研究中的应用。随着时间的推移提供强度不断增加的机电刺激的组织培养系统能够建立体外模型源自人类诱导多能干细胞的心脏组织具有成人心脏组织的许多特征。