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

Matthew J Birket, Marcelo C Ribeiro, Georgios Kosmidis, Dorien Ward, Ana Rita Leitoguinho, Vera van de Pol, Cheryl Dambrot, Harsha D Devalla, Richard P Davis, Pier G Mastroberardino, Douwe E Atsma, Robert Passier, Christine L Mummery

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)733-745
Number of pages13
JournalCell Reports
Volume13
Issue number4
DOIs
Publication statusPublished - 27 Oct 2015

Keywords

  • Animals
  • Cardiomyopathy, Hypertrophic
  • Carrier Proteins/genetics
  • Cell Differentiation
  • Cell Line
  • Electrophysiology
  • Flow Cytometry
  • Humans
  • Mice
  • Mutation/genetics
  • Myocytes, Cardiac/cytology
  • Pluripotent Stem Cells/cytology

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