title: Human Engineered Heart Tissue: Analysis of Contractile Force.
abstract: Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane- and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Ingra
authors.initials: I
authors.lastname: Mannhardt
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Kaja
authors.initials: K
authors.lastname: Breckwoldt
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Letuffe-Brenière
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schaaf
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine - MDC, DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 13092 Berlin, Germany; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Neuber
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Benzin
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Tessa
authors.initials: T
authors.lastname: Werner
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Eder
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schulze
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Klampe
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Marc N
authors.initials: MN
authors.lastname: Hirt
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine - MDC, DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 13092 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Huebner
authors.affiliation: I. Medical Department - Cardiology, Klinikum rechts der Isar - Technische Universität München, DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 81675 Munich, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Moretti
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, DZHK (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany. Electronic address: ar.hansen@uke.de.
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D006321:Heart / Q000254:growth & development*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008928:Mitochondria / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D012518:Sarcomeres / Q000378:metabolism; D023822:Tissue Engineering