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      Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies

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          Studying monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combine patient-derived and genetically engineered iPSCs with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene 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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          Most cited references 28

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          The Tension of Metallic Films Deposited by Electrolysis

           G. G. Stoney (1909)
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            hESC-Derived Cardiomyocytes Electrically Couple and Suppress Arrhythmias in Injured Hearts

            Transplantation studies in mice and rats have shown that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts 1–3 , but two critical issues related to their electrophysiological behavior in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear if these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea pig model to show hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia (VT). To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically-encoded calcium sensor, GCaMP3 4, 5 . By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host-graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.
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              Muscular thin films for building actuators and powering devices.

              We demonstrate the assembly of biohybrid materials from engineered tissues and synthetic polymer thin films. The constructs were built by culturing neonatal rat ventricular cardiomyocytes on polydimethylsiloxane thin films micropatterned with extracellular matrix proteins to promote spatially ordered, two-dimensional myogenesis. The constructs, termed muscular thin films, adopted functional, three-dimensional conformations when released from a thermally sensitive polymer substrate and were designed to perform biomimetic tasks by varying tissue architecture, thin-film shape, and electrical-pacing protocol. These centimeter-scale constructs perform functions as diverse as gripping, pumping, walking, and swimming with fine spatial and temporal control and generating specific forces as high as 4 millinewtons per square millimeter.

                Author and article information

                Nat Med
                Nat. Med.
                Nature medicine
                8 August 2014
                11 May 2014
                June 2014
                01 December 2014
                : 20
                : 6
                : 616-623
                [1 ]Department of Cardiology, Boston Children’s Hospital, Boston, MA, 02115, USA
                [2 ]Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA
                [3 ]Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA
                [4 ]Boston Children’s Hospital Department of Medicine, Division of Genetics, Boston Children’s Hospital, Boston, MA, 02115, USA
                [5 ]Allele Biotechnology & Pharmaceuticals, Inc., San Diego, CA, 92121, USA
                [6 ]Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Disease, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands
                [7 ]Department of Pathology, Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, 98109, USA
                [8 ]Departments of Bioengineering and Medicine/Cardiology, University of Washington, Seattle, WA, 98109, USA
                [9 ]Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, 17177, Stockholm, Sweden
                [10 ]Division of Metabolism, Kennedy Krieger Institute, Baltimore, MD, 21205, USA
                [11 ]Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA
                Author notes
                [¥ ]Correspondence to: W.T.P. 300 Longwood Ave, Boston, MA 02115, USA. wpu@ . Phone: 617-919-2091. Fax: 617-730-0140. K.K.P. 29 Oxford Street, Pierce Hall Cambridge, MA 02130, USA. kkparker@ . Phone: 617-495-2850. Fax: 617-496-1793

                contributed equally




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