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      Advanced maturation of human cardiac tissue grown from pluripotent stem cells

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          Abstract

          Cardiac tissues generated from human induced pluripotent stem (iPS) cells can serve as platforms for patient-specific studies of physiology and disease 16 . The predictive power of these models remains limited by their immature state 1, 2, 5, 6 . We show that this fundamental limitation could be overcome if cardiac tissues are formed from early iPS-derived cardiomyocytes (iPS-CM), soon after the initiation of spontaneous contractions, and subjected to physical conditioning of an increasing intensity. After only 4 weeks of culture, these tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiologic sarcomere length (2.2 μm) and density of mitochondria (30%), the presence of transverse tubules (t-tubules), oxidative metabolism, positive force-frequency relationship, and functional calcium handling for all iPS cell lines studied. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiologic responses to isoproterenol and recapitulating pathological hypertrophy, in support of the utility of this tissue model for studies of cardiac development and disease.

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          Most cited references21

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          Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation.

          Dramatic maturational changes occur in cardiac energy metabolism during cardiac development, differentiation, and postnatal growth. These changes in energy metabolism have important impacts on the ability of the cardiomyocyte to proliferate during early cardiac development, as well as when cardiomyocytes terminally differentiate during later development. During early cardiac development, glycolysis is a major source of energy for proliferating cardiomyocytes. As cardiomyocytes mature and become terminally differentiated, mitochondrial oxidative capacity increases, with fatty acid beta-oxidation becoming a major source of energy for the heart. The increase in mitochondrial oxidative capacity seems to coincide with a decrease in the proliferative ability of the cardiomyocyte. The switch from glycolysis to mitochondrial oxidative metabolism during cardiac development includes both alterations in the transcriptional control and acute alterations in the control of each pathway. Interestingly, if a hypertrophic stress is placed on the adult heart, cardiac energy metabolism switches to a more fetal phenotype, which includes an increase in glycolysis and decrease in mitochondrial fatty acid beta-oxidation. In this article, we review the impact of alterations in energy substrate metabolism on cardiomyocyte proliferation, differentiation, and postnatal maturation.
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            Using iPS cells to investigate cardiac phenotypes in patients with Timothy Syndrome

            Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life threatening ventricular arrhythmia 1, 2. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors1, 3. A missense mutation in the L-type calcium channel CaV1.2 leads to LQTS in patients with Timothy syndrome (TS)4, 5. To explore the effect of the TS mutation on the electrical activity and contraction of human cardiomyocytes (CMs), we reprogrammed human skin cells from TS patients to generate induced pluripotent stem cells (iPSCs), and differentiated these cells into CMs. Electrophysiological recording and calcium (Ca2+) imaging studies of these cells revealed irregular contraction, excess Ca2+ influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine (Ros), a compound that increases the voltage-dependent inactivation (VDI) of CaV1.26–8, restored the electrical and Ca2+ signaling properties of CMs from TS patients. This study opens new avenues for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.
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              Induced pluripotent stem cells: the new patient?

              Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular, neural and metabolic systems. This has not been met by commensurate development of new drugs and therapies, which is in part owing to the difficulty in modelling human diseases in laboratory assays or experimental animals. Patient-specific induced pluripotent stem (iPS) cells are an emerging paradigm that may address this. Reprogrammed somatic cells from patients are already applied in disease modelling, drug testing and drug discovery, thus enabling researchers to undertake studies for treating diseases 'in a dish', which was previously inconceivable.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                28 February 2018
                04 April 2018
                April 2018
                04 October 2018
                : 556
                : 7700
                : 239-243
                Affiliations
                [1 ]Laboratory for Stem Cells and Tissue Engineering, Department of Biomedical Engineering, Columbia University, New York, NY
                [2 ]Department of Rehabilitation and Regenerative Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY
                [3 ]Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
                [4 ]ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal
                [5 ]Department of Medicine, Columbia University, New York, NY
                Author notes
                [* ]Please address correspondence to: Gordana Vunjak-Novakovic, Columbia University, 622 West 168th Street, VC12-234, New York NY 10032, Tel: 212 305 2304; gv2131@ 123456columbia.edu

                Correspondence and requests for materials should be addressed to G.V.N. ( gv2131@ 123456columbia.edu ).

                Article
                NIHMS946860
                10.1038/s41586-018-0016-3
                5895513
                29618819
                dfb22a66-d74b-48ea-879e-a16db4cb9c09

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