Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes.
Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes.
复制标题
DOI：
10.1016/j.stemcr.2021.01.007
复制
发表时间：
2021-03-09
影响因子：
5.9
通讯作者：
Helms AS
中科院分区：
文献类型：
--
作者：
Ufford K;Friedline S;Tong Z;Tang VT;Dobbs AS;Tsan YC;Bielas SL;Liu AP;Helms AS
使用诱导多能干细胞(IPSC-CMS)来源的心肌细胞(IPSC-CMS)进行疾病建模和药物测试需要准确评估收缩功能。弹性衬底上的微图案化IPSC-CMS控制细胞的形状和排列，以进行收缩研究，但该系统中内在可变性的决定因素尚未完全确定。本研究的目的是确定肌原纤维结构对IPSC-CMS患者收缩功能的影响。对标记了细胞F-肌动蛋白染料的微图案IPSC-CMS的自动分析表明，肌原纤维的丰度在IPSC-CMS中差异很大，并且与收缩功能密切相关。这种可变性不能通过从单个IPSC亚克隆来减少，并且独立于IPSC-CM纯化方法。对肌原纤维结构的控制减少了与批次效应相关的假阳性发现，并提高了药理测试和疾病建模的敏感性。这一分析提供了令人信服的证据，表明在研究IPSC-CMS的收缩功能时，应该同时评估肌原纤维结构。IPSC-心肌细胞(IPSC-CMS)表现出显著的收缩功能变异，肌原纤维结构和丰度与IPSC-CM收缩功能相关，肌原纤维变异不会因单细胞亚克隆而减少，肌原纤维结构的控制对IPSC-CM收缩研究很重要，收缩功能是IPSC-CM的关键表型，但跨细胞变异限制了其在疾病建模和药理学试验中的应用。利用肌原纤维和牵引力的活细胞成像，Helms和他的同事证明了收缩功能依赖于可变的肌原纤维结构。因此，同时评估肌原纤维结构对于IPSC-CM收缩研究是重要的。
Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cells (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 the 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. iPSC-cardiomyocytes (iPSC-CMs) exhibit marked variability in contractile function Myofibrillar structure and abundance correlates with iPSC-CM contractile function Myofibrillar variability is not diminished by single-cell subcloning Controlling for myofibrillar structure is important for iPSC-CM contractile studies Contractile function is a critical phenotype of iPSC-derived cardiomyocytes (iPSC-CMs), but variability across cells limits application for disease modeling and pharmacologic testing. Using live-cell imaging of myofibrils and traction forces, Helms and colleagues demonstrate that contractile function is dependent on variable myofibrillar structure. Concurrent assessment of myofibrillar structure is therefore important for iPSC-CM contractile studies.
登录
查看更多内容
影响因子：
--
作者：
Burridge PW;Holmström A;Wu JC
通讯作者：
Wu JC
影响因子：
--
作者：
Bray, Mark-Anthony;Sheehy, Sean P.;Parker, Kevin Kit
通讯作者：
Parker, Kevin Kit
DOI：
10.1073/pnas.1508073112
发表时间：
2015-10-13
影响因子：
11.1
作者：
Ribeiro, Alexandre J. S.;Ang, Yen-Sin;Pruitt, Beth L.
通讯作者：
Pruitt, Beth L.
影响因子：
8
作者：
Helms, Adam S.;Tang, Vi T.;Day, Sharlene M.
通讯作者：
Day, Sharlene M.
影响因子：
6.1
作者：
Grevesse, Thomas;Versaevel, Marie;Gabriele, Sylvain
通讯作者：
Gabriele, Sylvain