Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies

Gang Wang, Megan L. McCain, Luhan Yang, Aibin He, Francesco Silvio Pasqualini, Ashutosh Agarwal, Hongyan Yuan, Dawei Jiang, Donghui Zhang, Lior Zangi, Judith Geva, Amy E. Roberts, Qing Ma, Jian Ding, Jinghai Chen, Da Zhi Wang, Kai Li, Jiwu Wang, Ronald J A Wanders, Wim Kulik & 8 others Frédéric M. Vaz, Michael A. Laflamme, Charles E. Murry, Kenneth R. Chien, Richard I. Kelley, George M. Church, Kevin Kit Parker, William T. Pu

Research output: Contribution to journalArticle

334 Citations (Scopus)

Abstract

Study of monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combined patient-derived and genetically engineered induced pluripotent stem cells (iPSCs) with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies and advances iPSC-based in vitro modeling of cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)616-623
Number of pages8
JournalNature Medicine
Volume20
Issue number6
DOIs
StatePublished - 2014
Externally publishedYes

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Barth Syndrome
Induced Pluripotent Stem Cells
Stem cells
Cardiomyopathies
Technology
Sarcomeres
Mutation
Cardiac Myocytes
Genes
Gene encoding
Myocardial Contraction
Mitochondrial Diseases
Tissue engineering
Reactive Oxygen Species
Tissue Engineering
Adenosine Triphosphate
Tissue
Heart Diseases
Phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. / Wang, Gang; McCain, Megan L.; Yang, Luhan; He, Aibin; Pasqualini, Francesco Silvio; Agarwal, Ashutosh; Yuan, Hongyan; Jiang, Dawei; Zhang, Donghui; Zangi, Lior; Geva, Judith; Roberts, Amy E.; Ma, Qing; Ding, Jian; Chen, Jinghai; Wang, Da Zhi; Li, Kai; Wang, Jiwu; Wanders, Ronald J A; Kulik, Wim; Vaz, Frédéric M.; Laflamme, Michael A.; Murry, Charles E.; Chien, Kenneth R.; Kelley, Richard I.; Church, George M.; Parker, Kevin Kit; Pu, William T.

In: Nature Medicine, Vol. 20, No. 6, 2014, p. 616-623.

Research output: Contribution to journalArticle

Wang, G, McCain, ML, Yang, L, He, A, Pasqualini, FS, Agarwal, A, Yuan, H, Jiang, D, Zhang, D, Zangi, L, Geva, J, Roberts, AE, Ma, Q, Ding, J, Chen, J, Wang, DZ, Li, K, Wang, J, Wanders, RJA, Kulik, W, Vaz, FM, Laflamme, MA, Murry, CE, Chien, KR, Kelley, RI, Church, GM, Parker, KK & Pu, WT 2014, 'Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies', Nature Medicine, vol. 20, no. 6, pp. 616-623. https://doi.org/10.1038/nm.3545
Wang, Gang ; McCain, Megan L. ; Yang, Luhan ; He, Aibin ; Pasqualini, Francesco Silvio ; Agarwal, Ashutosh ; Yuan, Hongyan ; Jiang, Dawei ; Zhang, Donghui ; Zangi, Lior ; Geva, Judith ; Roberts, Amy E. ; Ma, Qing ; Ding, Jian ; Chen, Jinghai ; Wang, Da Zhi ; Li, Kai ; Wang, Jiwu ; Wanders, Ronald J A ; Kulik, Wim ; Vaz, Frédéric M. ; Laflamme, Michael A. ; Murry, Charles E. ; Chien, Kenneth R. ; Kelley, Richard I. ; Church, George M. ; Parker, Kevin Kit ; Pu, William T. / Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. In: Nature Medicine. 2014 ; Vol. 20, No. 6. pp. 616-623.
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AU - Laflamme, Michael A.

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