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; Frédéric M Vaz; Michael A Laflamme; Charles E Murry; Kenneth R Chien; Richard I Kelley; George M Church; Kevin Kit Parker; William T Pu

doi:10.1038/nm.3545

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

Journal article

Open access

Peer reviewed

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, …

Nature medicine, Vol.20(6), pp.616-623

2014-06

DOI: https://doi.org/10.1038/nm.3545

PMID: 24813252

Abstract

Cardiomyopathy, Dilated - genetics

Mitochondrial Diseases - genetics

Reactive Oxygen Species - metabolism

Tissue Engineering - methods

Induced Pluripotent Stem Cells - physiology

Cell Separation

Humans

Myocardial Contraction - physiology

Transcription Factors - genetics

Magnetics

Barth Syndrome - genetics

Cardiomyopathy, Dilated - physiopathology

Models, Biological

Myocytes, Cardiac - physiology

Barth Syndrome - physiopathology

Mitochondrial Diseases - physiopathology

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.102 Stem Cell Research; 1.102.622 Pluripotency
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental
ESI research areas: Molecular Biology & Genetics

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Title: Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies
Creators: Gang Wang - 1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
Megan L McCain - 1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Luhan Yang - 1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
Aibin He - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Francesco Silvio Pasqualini - Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
Ashutosh Agarwal - Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
Hongyan Yuan - Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
Dawei Jiang - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Donghui Zhang - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Lior Zangi - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Judith Geva - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Amy E Roberts - 1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA
Qing Ma - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Jian Ding - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Jinghai Chen - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Da-Zhi Wang - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Kai Li - Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Jiwu Wang - 1] Allele Biotechnology & Pharmaceuticals, Inc., San Diego, California, USA. Department of Photobiology and Bioengineering, The Scintillon Institute, San Diego, California, USA
Ronald J A Wanders - Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
Wim Kulik - Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
Frédéric M Vaz - Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
Michael A Laflamme - Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
Charles E Murry - 1] Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. Department of Bioengineering, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. Department of Medicine and Cardiology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
Kenneth R Chien - Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, Stockholm, Sweden
Richard I Kelley - Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland, USA
George M Church - 1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
Kevin Kit Parker - 1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
William T Pu - 1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
Publication Details: Nature medicine, Vol.20(6), pp.616-623
Publisher: United States
Grant note: U01 HL100408 / NHLBI NIH HHS RC1 HL099618 / NHLBI NIH HHS UH3 TR000522 / NCATS NIH HHS UH2 TR000522 / NCATS NIH HHS U01 HL100401 / NHLBI NIH HHS T32 HL007572 / NHLBI NIH HHS
Academic Unit: College of Engineering; CoE - Biomedical Engineering
Language: English
Resource Type: Journal article
PMID: 24813252
Record Identifier: 991031559270602976