Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy

Ning Sun, Masayuki Yazawa, Jianwei Liu, Leng Han, Veronica Sanchez-Freire, Oscar J. Abilez, Enrique G. Navarrete, Shijun Hu, Li Wang, Andrew Lee, Aleksandra Pavlovic, Shin Lin, Rui Chen, Roger J. Hajjar, Michael P. Snyder, Ricardo E. Dolmetsch, Manish J. Butte, Euan A. Ashley, Michael T. Longaker, Robert C. RobbinsJoseph C. Wu

Research output: Contribution to journalArticlepeer-review

483 Scopus citations

Abstract

Characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in patients. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific cellular models, investigating underlying mechanisms, and optimizing therapy. Here, we generated cardiomyocytes from iPSCs derived from patients in a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to control healthy individuals in the same family cohort, cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca2+), decreased contractility, and abnormal distribution of sarcomeric a-actinin. When stimulated with a β-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric α-actinin distribution. Treatment with β-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca2+ adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients. Thus, iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM and may serve as a useful platform for exploring disease mechanisms and for drug screening.

Original languageEnglish
Article number130ra47
JournalScience Translational Medicine
Volume4
Issue number130
DOIs
StatePublished - 18 Apr 2012
Externally publishedYes

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