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      Modeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures

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          Abstract

          In the last decade, the generation of cardiac disease models based on human-induced pluripotent stem cells (hiPSCs) has become of common use, providing new opportunities to overcome the lack of appropriate cardiac models. Although much progress has been made toward the generation of hiPSC-derived cardiomyocytes (hiPS-CMs), several lines of evidence indicate that two-dimensional (2D) cell culturing presents significant limitations, including hiPS-CMs immaturity and the absence of interaction between different cell types and the extracellular matrix. More recently, new advances in bioengineering and co-culture systems have allowed the generation of three-dimensional (3D) constructs based on hiPSC-derived cells. Within these systems, biochemical and physical stimuli influence the maturation of hiPS-CMs, which can show structural and functional properties more similar to those present in adult cardiomyocytes. In this review, we describe the latest advances in 2D- and 3D-hiPSC technology for cardiac disease mechanisms investigation, drug development, and therapeutic studies.

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          3D Printing of Personalized Thick and Perfusable Cardiac Patches and Hearts

          Abstract Generation of thick vascularized tissues that fully match the patient still remains an unmet challenge in cardiac tissue engineering. Here, a simple approach to 3D‐print thick, vascularized, and perfusable cardiac patches that completely match the immunological, cellular, biochemical, and anatomical properties of the patient is reported. To this end, a biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to become pluripotent stem cells, and differentiated to cardiomyocytes and endothelial cells, the extracellular matrix is processed into a personalized hydrogel. Following, the two cell types are separately combined with hydrogels to form bioinks for the parenchymal cardiac tissue and blood vessels. The ability to print functional vascularized patches according to the patient's anatomy is demonstrated. Blood vessel architecture is further improved by mathematical modeling of oxygen transfer. The structure and function of the patches are studied in vitro, and cardiac cell morphology is assessed after transplantation, revealing elongated cardiomyocytes with massive actinin striation. Finally, as a proof of concept, cellularized human hearts with a natural architecture are printed. These results demonstrate the potential of the approach for engineering personalized tissues and organs, or for drug screening in an appropriate anatomical structure and patient‐specific biochemical microenvironment.
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            The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology.

            The environment in which the field of cardiology finds itself has been rapidly changing. This supplement, an expansion of a report created for the Board of Trustees, is intended to provide a timely snapshot of the socio-economic, political, and scientific aspects of this environment as it applies to practice both in the United States and internationally. This publication should assist healthcare professionals looking for the most recent statistics on cardiovascular disease and the risk factors that contribute to it, drug and device trends affecting the industry, and how the practice of cardiology is changing in the United States. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

              Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                11 May 2020
                May 2020
                : 21
                : 9
                : 3404
                Affiliations
                [1 ]Department of Molecular Genetics, University of Maastricht, Universiteitssingel 50, 6229ER Maastricht, The Netherlands; claudia.sacchetto.1@ 123456studenti.unipd.it (C.S.); L.deWindt@ 123456maastrichtuniversity.nl (L.J.d.W)
                [2 ]Department of Biology, University of Padova, via Ugo Bassi 58B, 35131 Padova, Italy; libero.vitiello@ 123456unipd.it
                [3 ]Interuniversity Institute of Myology (IIM), Administrative headquarters University of Perugia, Piazza Lucio Severi 1, 06132 Perugia, Italy
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-0017-0838
                https://orcid.org/0000-0002-7793-2856
                https://orcid.org/0000-0003-3884-8843
                Article
                ijms-21-03404
                10.3390/ijms21093404
                7246991
                32403456
                e6c91e70-b4de-4ef3-9db9-3cd5d8acb952
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 April 2020
                : 06 May 2020
                Categories
                Review

                Molecular biology
                cardiac disease modeling,human induced pluripotent stem cells,3d cardiac models,engineered heart tissue

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