Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium

Irene C. Turnbull, Ioannis Karakikes, Gregory W. Serrao, Peter Backeris, Jia Jye Lee, Chaoqin Xie, Grant Senyei, Ronald E. Gordon, Ronald A. Li, Fadi G. Akar, Roger J. Hajjar, Jean Sébastien Hulot, Kevin D. Costa

Research output: Contribution to journalArticle

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/mm2 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.

Original languageEnglish (US)
Pages (from-to)644-654
Number of pages11
JournalFASEB Journal
Volume28
Issue number2
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Keywords

  • Cardiomyocyte development
  • Contractile function
  • Drug discovery
  • Stem cell

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Turnbull, I. C., Karakikes, I., Serrao, G. W., Backeris, P., Lee, J. J., Xie, C., ... Costa, K. D. (2014). Advancing functional engineered cardiac tissues toward a preclinical model of human myocardium. FASEB Journal, 28(2), 644-654. https://doi.org/10.1096/fj.13-228007