title: Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium.
abstract: Cardiac experimental biology and translational research would benefit from an in vitro surrogate for human heart muscle. This study investigated structural and functional properties and interventional responses of human engineered cardiac tissues (hECTs) compared to human myocardium. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs, >90% troponin-positive) were mixed with collagen and cultured on force-sensing elastomer devices. hECTs resembled trabecular muscle and beat spontaneously (1.18 ± 0.48 Hz). Microstructural features and mRNA expression of cardiac-specific genes (α-MHC, SERCA2a, and ACTC1) were comparable to human myocardium. Optical mapping revealed cardiac refractoriness with loss of 1:1 capture above 3 Hz, and cycle length dependence of the action potential duration, recapitulating key features of cardiac electrophysiology. hECTs reconstituted the Frank-Starling mechanism, generating an average maximum twitch stress of 660 μN/mm(2) at Lmax, approaching values in newborn human myocardium. Dose-response curves followed exponential pharmacodynamics models for calcium chloride (EC50 1.8 mM) and verapamil (IC50 0.61 μM); isoproterenol elicited a positive chronotropic but negligible inotropic response, suggesting sarcoplasmic reticulum immaturity. hECTs were amenable to gene transfer, demonstrated by successful transduction with Ad.GFP. Such 3-D hECTs recapitulate an early developmental stage of human myocardium and promise to offer an alternative preclinical model for cardiology research.
authors.affiliation: 2Cardiovascular Cell and Tissue Engineering Laboratory, Cardiovascular Research Center, Icahn School of Medicine at Mt. Sinai, One Gustave L. Levy Pl., P.O. Box 1030, New York, NY 10029, USA. kevin.costa@mssm.edu.
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Serrao
authors.forename: Peter
authors.initials: P
authors.lastname: Backeris
authors.forename: Jia-Jye
authors.initials: JJ
authors.lastname: Lee
authors.forename: Chaoqin
authors.initials: C
authors.lastname: Xie
authors.forename: Grant
authors.initials: G
authors.lastname: Senyei
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gordon
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Akar
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Costa
mesh_terms: D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D009206:Myocardium / Q000166:cytology*; D023822:Tissue Engineering / Q000379:methods*
keywords: cardiomyocyte development; contractile function; drug discovery; stem cell