Physiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform.
Physiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform.
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DOI：
10.1038/s41467-021-26496-1
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发表时间：
2021-10-25
影响因子：
16.6
通讯作者：
Helms AS
中科院分区：
文献类型：
--
作者：
Tsan YC;DePalma SJ;Zhao YT;Capilnasiu A;Wu YW;Elder B;Panse I;Ufford K;Matera DL;Friedline S;O'Leary TS;Wubshet N;Ho KKY;Previs MJ;Nordsletten D;Isom LL;Baker BM;Liu AP;Helms AS
人类多能干细胞衍生的心肌细胞（hPSC-CMs）允许在人类心脏模型系统中进行研究，但hPSC-CMs在标准二维表面上的无序力学和不成熟一直是障碍。在这里，我们开发了一个微米级心肌束的平台，以控制二维弹性体基质上数千个纯化的、独立收缩的心肌条阵列的生物力学，其吞吐量远高于单细胞方法。通过在这个简化平台中定义几何形状和工作量，我们表明，在生理工作量下，肌纤维排列和强直收缩驱动收缩功能、钙处理和电生理的成熟。利用转录组学、报告细胞hPSC-CMs和定量免疫荧光，这些心肌束可用于解析早期发育中的正交信号，包括收缩力、钙负荷和代谢信号。此外，由此产生的有组织的生物力学有助于从明场显微镜成像中自动提取收缩动力学，增加药理学测试和心肌病疾病建模的可及性、可重复性和吞吐量。涉及人类多能干细胞衍生的心肌细胞的人类心脏病的研究受到生物力学线索无序呈现导致细胞不成熟的限制。在这里，作者开发了一个微米级二维心肌束的平台，以精确地传递生理信号，提高再现性和吞吐量。
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) allow investigations in a human cardiac model system, but disorganized mechanics and immaturity of hPSC-CMs on standard two-dimensional surfaces have been hurdles. Here, we developed a platform of micron-scale cardiac muscle bundles to control biomechanics in arrays of thousands of purified, independently contracting cardiac muscle strips on two-dimensional elastomer substrates with far greater throughput than single cell methods. By defining geometry and workload in this reductionist platform, we show that myofibrillar alignment and auxotonic contractions at physiologic workload drive maturation of contractile function, calcium handling, and electrophysiology. Using transcriptomics, reporter hPSC-CMs, and quantitative immunofluorescence, these cardiac muscle bundles can be used to parse orthogonal cues in early development, including contractile force, calcium load, and metabolic signals. Additionally, the resultant organized biomechanics facilitates automated extraction of contractile kinetics from brightfield microscopy imaging, increasing the accessibility, reproducibility, and throughput of pharmacologic testing and cardiomyopathy disease modeling. Investigations of human cardiac disease involving human pluripotent stem cell-derived cardiomyocytes are limited by the disorganized presentation of biomechanical cues resulting in cell immaturity. Here the authors develop a platform of micron-scale 2D cardiac muscle bundles to precisely deliver physiologic cues, improving reproducibility and throughput.
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影响因子：
--
作者：
Bray, Mark-Anthony;Sheehy, Sean P.;Parker, Kevin Kit
通讯作者：
Parker, Kevin Kit
影响因子：
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作者：
Iseoka H;Miyagawa S;Fukushima S;Saito A;Masuda S;Yajima S;Ito E;Sougawa N;Takeda M;Harada A;Lee JK;Sawa Y
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Sawa Y
影响因子：
6.1
作者：
Grosberg A;Alford PW;McCain ML;Parker KK
通讯作者：
Parker KK
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：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.