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Toxicol Sci. 2019 Aug 6. pii: kfz168. doi: 10.1093/toxsci/kfz168. [Epub ahead of print]

Engineered Cardiac Tissues Generated in the Biowire™ II: A Platform for Human-Based Drug Discovery.

Author information

1
TARA Biosystems, New York, NY, USA.
2
GlaxoSmithKline, Collegeville, PA, USA.

Abstract

Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery and development studies. The Biowire™ II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-CMs and cardiac fibroblasts. Long term electrical stimulation was employed to obtain ECTs that possess a phenotype like that of adult human myocardium including a lack of spontaneous beating, the presence of a positive force-frequency response from 1-4Hz and prominent post-rest potentiation. Pharmacology studies were performed in the ECTs to confirm the presence and functionality of pathways that modulate cardiac contractility in humans. Canonical responses were observed for compounds that act via the β-adrenergic/cAMP-mediated pathway, e.g. isoproterenol and milrinone; the L-type calcium channel, e.g. FPL64176 and nifedipine; and indirectly effect intracellular Ca2+ concentrations, e.g. digoxin. Expected positive inotropic responses were observed for compounds that modulate proteins of the cardiac sarcomere, e.g. omecamtiv mecarbil and levosimendan. ECTs generated in the BiowireTM II platform display adult-like properties and have canonical responses to cardiotherapeutic and cardiotoxic agents that affect contractility in humans via a variety of mechanisms. These data demonstrate that this human-based model can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process.

KEYWORDS:

Cardiomyocytes; contractility; drug discovery; drug safety; engineered cardiac tissue; in vitro models

PMID:
31385592
DOI:
10.1093/toxsci/kfz168

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