title: Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies.
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.
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. [2].
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1] Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. [2].
authors.forename: Megan L
authors.initials: ML
authors.lastname: McCain
authors.affiliation: 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.
authors.forename: Luhan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Francesco Silvio
authors.identifier: 0000000170383121
authors.initials: FS
authors.lastname: Pasqualini
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Donghui
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Lior
authors.initials: L
authors.lastname: Zangi
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Geva
authors.affiliation: 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.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: 1] Allele Biotechnology & Pharmaceuticals, Inc., San Diego, California, USA. [2] Department of Photobiology and Bioengineering, The Scintillon Institute, San Diego, California, USA.
authors.forename: Jiwu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Kulik
authors.affiliation: Department of Clinical Chemistry and Pediatrics, Laboratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.affiliation: Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
authors.affiliation: 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.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.affiliation: Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.affiliation: Division of Metabolism, Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.affiliation: 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.
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.affiliation: 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.
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
authors.affiliation: 1] Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
mesh_terms: D000217:Acyltransferases; D056889:Barth Syndrome / Q000235:genetics / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology*; D002469:Cell Separation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008280:Magnetics; D028361:Mitochondrial Diseases / Q000235:genetics / Q000503:physiopathology*; D008954:Models, Biological; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human