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      ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure

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          Abstract

          Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.

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          Most cited references151

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          Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels.

          Gelatin methacryloyl (GelMA) hydrogels have been widely used for various biomedical applications due to their suitable biological properties and tunable physical characteristics. GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM) due to the presence of cell-attaching and matrix metalloproteinase responsive peptide motifs, which allow cells to proliferate and spread in GelMA-based scaffolds. GelMA is also versatile from a processing perspective. It crosslinks when exposed to light irradiation to form hydrogels with tunable mechanical properties. It can also be microfabricated using different methodologies including micromolding, photomasking, bioprinting, self-assembly, and microfluidic techniques to generate constructs with controlled architectures. Hybrid hydrogel systems can also be formed by mixing GelMA with nanoparticles such as carbon nanotubes and graphene oxide, and other polymers to form networks with desired combined properties and characteristics for specific biological applications. Recent research has demonstrated the proficiency of GelMA-based hydrogels in a wide range of tissue engineering applications including engineering of bone, cartilage, cardiac, and vascular tissues, among others. Other applications of GelMA hydrogels, besides tissue engineering, include fundamental cell research, cell signaling, drug and gene delivery, and bio-sensing.
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            Inducible apoptosis as a safety switch for adoptive cell therapy.

            Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
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              Advanced maturation of human cardiac tissue grown from pluripotent stem cells

              Cardiac tissues generated from human induced pluripotent stem (iPS) cells can serve as platforms for patient-specific studies of physiology and disease 1–6 . 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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                Author and article information

                Journal
                Cardiovascular Research
                Oxford University Press (OUP)
                0008-6363
                1755-3245
                March 01 2019
                March 01 2019
                January 17 2019
                March 01 2019
                March 01 2019
                January 17 2019
                : 115
                : 3
                : 488-500
                Affiliations
                [1 ]Institute of Cardiology and Center of Excellence on Aging, “G. d’Annunzio” University—Chieti, Italy
                [2 ]University of Texas Medical School in Houston, USA
                [3 ]Cardiology and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, The Netherlands
                [4 ]Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
                [5 ]The Hatter Cardiovascular Institute, University College London, London, UK
                [6 ]University of Pisa, Pisa University Hospital, Pisa, Italy
                [7 ]Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Muscle Research Center Erlangen, MURCE
                [8 ]Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Germany
                [9 ]DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany
                [10 ]Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain
                [11 ]CIBERCV, ISCIII, Madrid, Spain
                [12 ]Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore
                [13 ]National Heart Research Institute Singapore, National Heart Centre, Singapore
                [14 ]Yong Loo Lin School of Medicine, National University Singapore, Singapore
                [15 ]The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Research & Development, London, UK
                [16 ]Université Paris-Descartes, Sorbonne Paris Cité, Paris, France
                [17 ]Paris Cardiovascular Research Center (PARCC), INSERM UMRS 970, Paris, France
                [18 ]Hôpital Européen Georges Pompidou, AP-HP, Paris, France
                [19 ]Hatter Cardiovascular Research Institute, University of Cape Town, South Africa
                [20 ]Tamman and Neufeld Cardiovascular Research Institutes, Sackler Faculty of Medicine, Tel-Aviv University and Sheba Medical Center, Tel-Hashomer, Israel
                [21 ]Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Paris, France
                [22 ]INSERM UMRS 970, Paris, France
                [23 ]Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS, Milan, Italy
                [24 ]Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
                [25 ]Institut Mitovasc, INSERM, CNRS, Université d’Angers, Service de Cardiologie, CHU Angers, Angers, France
                [26 ]Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany
                [27 ]Department of Cardiology, Charité, University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany
                [28 ]DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
                [29 ]Department of Medical Biology, UiT, The Arctic University of Norway, Norway
                [30 ]Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany
                [31 ]DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
                [32 ]Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, III-V Floor, H-1089 Budapest, Hungary
                [33 ]Pharmahungary Group, Szeged, Hungary
                [34 ]Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX Utrecht, the Netherlands
                Article
                10.1093/cvr/cvz010
                6383054
                30657875
                b4a7e3cd-487f-4fe3-8dce-ea14ae12bb50
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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