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      Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration


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          The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue (EHT) in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human EHTs, while reducing passive stiffness compared to mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Co-transplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, co-transplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function make them a promising adjuvant therapeutic for cardiac repair.

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          Most cited references 36

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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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            Shattuck lecture--cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities.

             E Braunwald (1997)
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              Fate of the mammalian cardiac neural crest.

              A subpopulation of neural crest termed the cardiac neural crest is required in avian embryos to initiate reorganization of the outflow tract of the developing cardiovascular system. In mammalian embryos, it has not been previously experimentally possible to study the long-term fate of this population, although there is strong inference that a similar population exists and is perturbed in a number of genetic and teratogenic contexts. We have employed a two-component genetic system based on Cre/lox recombination to label indelibly the entire mouse neural crest population at the time of its formation, and to detect it at any time thereafter. Labeled cells are detected throughout gestation and in postnatal stages in major tissues that are known or predicted to be derived from neural crest. Labeling is highly specific and highly efficient. In the region of the heart, neural-crest-derived cells surround the pharyngeal arch arteries from the time of their formation and undergo an altered distribution coincident with the reorganization of these vessels. Labeled cells populate the aorticopulmonary septum and conotruncal cushions prior to and during overt septation of the outflow tract, and surround the thymus and thyroid as these organs form. Neural-crest-derived mesenchymal cells are abundantly distributed in midgestation (E9.5-12.5), and adult derivatives of the third, fourth and sixth pharyngeal arch arteries retain a substantial contribution of labeled cells. However, the population of neural-crest-derived cells that infiltrates the conotruncus and which surrounds the noncardiac pharyngeal organs is either overgrown or selectively eliminated as development proceeds, resulting for these tissues in a modest to marginal contribution in late fetal and postnatal life.

                Author and article information

                Nat Biotechnol
                Nat. Biotechnol.
                Nature biotechnology
                28 October 2019
                02 August 2019
                August 2019
                02 February 2020
                : 37
                : 8
                : 895-906
                [1 ]The Anne McLaren Laboratory, Wellcome Trust –MRC Cambridge Stem Cell Institute, Forvie Site, University of Cambridge, Robinson Way, Cambridge CB2 0SZ, UK
                [2 ]Division of Cardiovascular Medicine, University of Cambridge, ACCI Level 6, Box 110, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
                [3 ]Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, US
                [4 ]Babraham Institute, Babraham Hall, Babraham CB22 3AT, UK
                [5 ]Department of Bioengineering, University of Washington, Seattle, WA, US
                [6 ]Department of Medicine/Cardiology, University of Washington, Seattle, WA, US
                Author notes

                Equal Contributions

                Author contributions: JB: Principal experimentalist, study design and conceptualisation, data acquisition and interpretation, production of figures, manuscript writing; LPO: tissue culture, 3D-EHT generation, force measurement, assistance during surgery; MC: tissue culture, 3D-EHT generation; HD: force measurement and QRT-PCR; PH: preparation of cell suspension on the day of transplantation, necropsy, assistance during surgery, postoperative animal care; SB: casting of 3D-EHT, force measurement; LG: tissue histology, immunofluorescence, sample preparation for RNAseq; NLN: bioinformatics analysis; DI: conceptual ideas, critical revision of the manuscript for important intellectual content; FS: Critical revision of the manuscript for important intellectual content; FW: functional analysis of echocardiographs; AB: gene expression analysis; AL: experimental guidance and force measurement data analysis; WGB: data interpretation and logistics; AM: animal surgery and logistics; NF: processing of histologic tissue, preparation of slides; MR: force measurement equipment; MRB: critical revision of the manuscript for important intellectual content; CEM: design and concept of the study, obtaining research funding, study supervision, editing and final approval of the manuscript; SS: design and concept of the study, obtaining research funding, study supervision, interpretation of data, editing and final approval of the manuscript.

                Corresponding Authors: Dr. Sanjay Sinha, The Anne McLaren Laboratory, WT-MRC Cambridge Stem Cell Institute, West Forvie Building, Forvie Site, University of Cambridge, Robinson Way, CB2 0SZ Cambridge, UK, Tel.: +44 1223 747479, Fax: +44 1223 763350., ss661@ 123456cam.ac.uk , Dr. Charles E. Murry, Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA, Tel: +1-206-616-8685, Fax: +1-206-897-1540, murry@ 123456uw.edu

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