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

• Published in: Nature medicine Vol. 20; no. 6; pp. 616 - 623
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2014; Nature Publishing Group
• Subjects: 13/100; 13/107; 42/109; 45/41; 631/443/592/75/74; 9/10; ATP; Barth syndrome; Barth Syndrome - genetics; Barth Syndrome - physiopathology; Biomedicine; Cancer Research; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - physiopathology; Cell Separation; Complications and side effects; Development and progression; Genetic aspects; Genetic disorders; Heart diseases; Humans; Induced Pluripotent Stem Cells - physiology; Infectious Diseases; Magnetics; Metabolic Diseases; Mitochondrial Diseases - genetics; Mitochondrial Diseases - physiopathology; Models, Biological; Molecular Medicine; Mutation; Myocardial Contraction - physiology; Myocytes, Cardiac - physiology; Neurosciences; Pathogenesis; Physiological aspects; Reactive Oxygen Species - metabolism; Risk factors; Stem cells; Tissue engineering; Tissue Engineering - methods; Transcription Factors - genetics; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3545

Cardiomyocytes generated from induced pluripotent cells hold great promise for understanding and treating heart disease. William Pu and his colleagues apply new technologies for studying such cardiomyocytes from patients with Barth syndrome to explore how the mitochondrial defects characteristic of this syndrome lead to heart dysfunction. 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.