Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells

Feng Lan, Andrew S. Lee, Ping Liang, Veronica Sanchez-Freire, Patricia K. Nguyen, Li Wang, Leng Han, Michelle Yen, Yongming Wang, Ning Sun, Oscar J. Abilez, Shijun Hu, Antje D. Ebert, Enrique G. Navarrete, Chelsey S. Simmons, Matthew Wheeler, Beth Pruitt, Richard Lewis, Yoshinori Yamaguchi, Euan A. AshleyDonald M Bers, Robert C. Robbins, Michael T. Longaker, Joseph C. Wu

Research output: Contribution to journalArticle

317 Scopus citations

Abstract

Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca2+) imaging indicated dysregulation of Ca2+ cycling and elevation in intracellular Ca2+ ([Ca2+] i) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca2+ homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

Original languageEnglish (US)
Pages (from-to)101-113
Number of pages13
JournalCell Stem Cell
Volume12
Issue number1
DOIs
StatePublished - Jan 3 2013

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ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Lan, F., Lee, A. S., Liang, P., Sanchez-Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., Wang, Y., Sun, N., Abilez, O. J., Hu, S., Ebert, A. D., Navarrete, E. G., Simmons, C. S., Wheeler, M., Pruitt, B., Lewis, R., Yamaguchi, Y., ... Wu, J. C. (2013). Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell, 12(1), 101-113. https://doi.org/10.1016/j.stem.2012.10.010