Laboratory for Stem Cells and Tissue Engineering, Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Department of Rehabilitation and Regenerative Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Nature. 2018 Apr;556(7700):239-243. doi: 10.1038/s41586-018-0016-3. Epub 2018 Apr 4.
Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease. However, the predictive power of these models is presently limited by the immature state of the cells. 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.
由人诱导多能干细胞 (iPSC) 生成的心脏组织可以作为研究生理和疾病的患者特异性模型。然而，这些模型的预测能力目前受到细胞不成熟状态的限制。在这里，我们表明，如果在自发性收缩开始后不久，从早期 iPSC 衍生的心肌细胞中形成心脏组织，并随着时间的推移逐渐增加强度进行物理条件训练，就可以克服这一基本限制。在仅培养四周后，对于所有研究的 iPSC 系，这些组织均表现出类似成人的基因表达谱、显著的超微结构组织、生理肌节长度（2.2μm）和线粒体密度（30%）、横管的存在、氧化代谢、正向力频率关系和功能钙处理。机电特性的发展较慢，并且没有达到成年人心肌中看到的成熟阶段。组织成熟对于实现异丙肾上腺素的生理反应和再现病理性肥大是必要的，这支持了该组织模型在心脏发育和疾病研究中的应用。
