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Nat Med. 2014 Jun;20(6):616-23. doi: 10.1038/nm.3545. Epub 2014 May 11.

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

Author information

1
1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. [2].
2
1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2].
3
1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
5
Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
6
1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA.
7
1] Allele Biotechnology & Pharmaceuticals, Inc., San Diego, California, USA. [2] Department of Photobiology and Bioengineering, The Scintillon Institute, San Diego, California, USA.
8
Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
9
Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
10
1] Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Bioengineering, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. [3] Department of Medicine and Cardiology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
11
Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, Stockholm, Sweden.
12
Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland, USA.
13
1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
14
1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

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.

PMID:
24813252
PMCID:
PMC4172922
DOI:
10.1038/nm.3545
[Indexed for MEDLINE]
Free PMC Article

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