Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) requires accurate assessment of contractile function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable contractile studies, but determinants of intrinsic variability in this system have been incompletely characterized. The objective of this study was to determine the impact of myofibrillar structure on contractile function in iPSC-CMs. Automated analysis of micropatterned iPSC-CMs labeled with a cell permeant F-actin dye revealed that myofibrillar abundance is widely variable among iPSC-CMs and strongly correlates with contractile function. This variability is not reduced by subcloning from single iPSCs and is independent of iPSC-CM purification method. Controlling for myofibrillar structure reduces false positive findings related to batch effect and improves sensitivity for pharmacologic testing and disease modeling. This analysis provides compelling evidence that myofibrillar structure should be assessed concurrently in studies investigating contractile function in iPSC-CMs.

中文翻译：

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肌原纤维的结构变异性是干细胞衍生心肌细胞收缩功能的基础

使用诱导多能干细胞（iPSC-CMs）衍生的心肌细胞进行疾病建模和药物测试，需要准确评估其收缩功能。在弹性基材上进行微图案化iPSC-CM可以控制细胞的形状和排列，以进行可收缩的研究，但是该系统内在变异性的决定因素尚未完全表征。这项研究的目的是确定肌原纤维结构对iPSC-CMs收缩功能的影响。对带有细胞渗透性F-肌动蛋白染料标记的微图案化iPSC-CM的自动分析显示，肌原纤维丰度在iPSC-CM之间存在很大差异，并且与收缩功能密切相关。通过从单个iPSC进行亚克隆不会降低这种变异性，并且独立于iPSC-CM纯化方法。控制肌原纤维结构可减少与批量效应相关的假阳性结果，并提高药理学测试和疾病建模的敏感性。该分析提供了令人信服的证据，即在研究iPSC-CMs收缩功能的研究中应同时评估肌原纤维的结构。