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Cell Rep. 2015 Oct 27;13(4):733-745. doi: 10.1016/j.celrep.2015.09.025. Epub 2015 Oct 17.

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

Author information

1
Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
2
Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
3
Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands.
4
Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
5
Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands. Electronic address: c.l.mummery@lumc.nl.

Abstract

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.

PMID:
26489474
PMCID:
PMC4644234
DOI:
10.1016/j.celrep.2015.09.025
[Indexed for MEDLINE]
Free PMC Article

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