Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function

被引：152

作者：

Birket, Matthew J. ^{[1
]}

Ribeiro, Marcelo C. ^{[1
]}

Kosmidis, Georgios ^{[1
]}

Ward, Dorien ^{[1
]}

Leitoguinho, Ana Rita ^{[1
]}

van de Pol, Vera ^{[1
]}

Dambrot, Cheryl ^{[1
,2
]}

Devalla, Harsha D. ^{[1
]}

Davis, Richard P. ^{[1
]}

Mastroberardino, Pier G. ^{[3
]}

Atsma, Douwe E. ^{[2
]}

Passier, Robert ^{[1
]}

Mummery, Christine L. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Anat & Embryol, NL-2300 RC Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands

[3] Erasmus MC, NL-3015 GE Rotterdam, Netherlands

来源：

CELL REPORTS | 2015年 / 13卷 / 04期

基金：

欧洲研究理事会;

关键词：

PLURIPOTENT STEM-CELL; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; BINDING PROTEIN-C; PIG VENTRICULAR MYOCYTES; CARDIAC SODIUM-CHANNEL; GROWTH-FACTOR-I; THYROID-HORMONE; HEART-TISSUE; MATURATION; CALCIUM;

D O I：

10.1016/j.celrep.2015.09.025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.

引用

页码：733 / 745

页数：13

共 66 条

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