The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells’ action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells’ mitochondrial structure and calcium handling, and observed divergent cell-source-dependent effects on action-potential duration (APD). Specifically, in the presence of maturation media, tissues with abnormally prolonged APDs exhibited shorter APDs, and tissues with aberrantly short APDs displayed prolonged APDs. Regardless of cell source, tissue maturation reduced variabilities in spontaneous beat rate and in APD, and led to converging cell phenotypes (with APDs within the 300–450 ms range characteristic of human left ventricular cardiomyocytes) that improved the modelling of the effects of pro-arrhythmic drugs on cardiac tissue.

源自人类诱导多能干细胞 (hiPSC) 的心肌细胞的不成熟生理学限制了其在药物筛选和疾病建模中的实用性。在这里，我们表明机械刺激和代谢线索的适当组合可以增强 hiPSC 来源的心肌细胞的成熟，并且成熟诱导线索对细胞的动作电位形态和钙处理具有表型依赖性影响。通过使用微流控芯片增强来自 hiPSC 来源的心肌细胞的遗传上不同来源的心脏微组织的排列和细胞外基质的产生，我们确定了富含脂肪酸的成熟培养基，可以改善细胞的线粒体结构和钙处理，并观察到不同的对动作电位持续时间（APD）的细胞来源依赖性影响。具体来说，在存在成熟培养基的情况下，APD 异常延长的组织表现出较短的 APD，而 APD 异常短的组织则表现出延长的 APD。无论细胞来源如何，组织成熟都会减少自发搏动率和 APD 的变异性，并导致细胞表型趋同（APD 在人类左心室心肌细胞特有的 300-450 ms 范围内），从而改善了亲细胞效应的建模。对心脏组织的抗心律失常药物。