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Combining physiological relevance and throughput for in vitro cardiac contractility measurement

  • Despite increasing acceptance of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in safety pharmacology, controversy remains about the physiological relevance of existing in vitro models for their mechanical testing. We hypothesize that existing signs of immaturity of the cell models result from an improper mechanical environment. We cultured hiPSC-CMs in a 96-well format on hyperelastic silicone membranes imitating their native mechanical environment, resulting in physiological responses to compound stimuli.We validated cell responses on the FLEXcyte 96, with a set of reference compounds covering a broad range of cellular targets, including ion channel modulators, adrenergic receptor modulators and kinase inhibitors. Acute (10 - 30 min) and chronic (up to 7 days) effects were investigated. Furthermore, the measurements were complemented with electromechanical models based on electrophysiological recordings of the used cell types.hiPSC-CMs were cultured on freely-swinging, ultra-thin and hyperelastic silicone membranes. The weight of the cell culture medium deflects the membranes downwards. Rhythmic contraction of the hiPSC-CMs resulted in dynamic deflection changes which were quantified by capacitive distance sensing. The cells were cultured for 7 days prior to compound addition. Acute measurements were conducted 10-30 minutes after compound addition in standard culture medium. For chronic treatment, compound-containing medium was replaced daily for up to 7 days. Electrophysiological properties of the employed cell types were recorded by automated patch-clamp (Patchliner) and the results were integrated into the electromechanical model of the system.Calcium channel agonist S Bay K8644 and beta-adrenergic stimulator isoproterenol induced significant positive inotropic responses without additional external stimulation. Kinase inhibitors displayed cardiotoxic effects on a functional level at low concentrations. The system-integrated analysis detected alterations in beating shape as well as frequency and arrhythmic events and we provide a quantitative measure of these.

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Metadaten
Author:Ronald Knox, Andrea Bruggemann, Matthias Gossmann, Ulrich Thomas, András Horváth, Elena Dragicevic, Sonja Stoelzle-Feix, Niels Fertig, Alexander JungORCiD, Aravind Hariharan RamanORCiD, Manfred StaatORCiD, Peter LinderORCiD
DOI:https://doi.org/10.1016/j.bpj.2019.11.3104
ISSN:0006-3495
Parent Title (English):Biophysical Journal
Publisher:Elsevier
Place of publication:Amsterdam
Document Type:Article
Language:English
Year of Completion:2020
Date of the Publication (Server):2020/02/14
Volume:118
Issue:Issue 3, Supplement 1
First Page:570a
Note:
Raman, Arayind Hariharan 
im Artikel unter dem Namen: Raman, Alexander H.
Link:https://doi.org/10.1016/j.bpj.2019.11.3104
Zugriffsart:bezahl
Institutes:FH Aachen / Fachbereich Medizintechnik und Technomathematik
FH Aachen / IfB - Institut für Bioengineering
collections:Verlag / Elsevier