Mechano-Pharmacological Characterization of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells

Abstract

Background/Aims: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. Methods: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS-CMs induced variations of the membrane deflection. The recorded contraction-relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca²⁺ channels (S-Bay K8644/verapamil) and Na⁺ channels (veratridine/lidocaine). Results: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose-response curves were highly accurate and consistent with reference data. Conclusion: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential.

Modeling and simulation of human induced pluripotent stem cell‐derived cardiac tissue

“…Blocking effects on I CaL change the shape of the displacement‐time curve and decrease its amplitude as shown in Figure and Table . This is consistent with other computational and experimental studies where hiPSC‐CMs were used. The APD90 is found to decrease (Table ), which was also found in a recently published computational and experimental study with the Cor.4U cell line .…”

“…MEA measures the extracellular field potential and based on that the conduction speed (CS) of the action potential throughout the tissue can be derived. The CellDrum was developed in our institute and is used for mechanical measurements. It is a circular well (radius r = 3.2 mm) in which the tissue construct (silicone membrane and cell monolayer) is clamped.…”

The Construction and Identification of Induced Pluripotent Stem Cells Derived from Acute Myelogenous Leukemia Cells

“…Moreover, a previous study has demonstrated that iPSCs possess the characteristics of embryonic stem cells [24], and embryonic stem cells have also been demonstrated to have an unlimited proliferative potential as well as the ability to differentiate into almost any type of tissue [25]. Because of this, iPSCs have a stronger ability to proliferate than differentiated cells and were predicted to be transferred into adult cells via parallel mathematical modeling and numerical simulation [26]. Studies have shown that in successfully induced stem cells with a differentiation potential, a number of embryonic stem cell protein markers such as NANOG, SSEA-3, SSEA-4, TRA-1-60 and TRA-1-81 are expressed [27-29], wherein SSEA-3 and SSEA-4 are cell membrane proteins, TRA-1-60 and TRA-1-81 are cytoplasmic proteins, and NANOG is a cell nuclear protein [30-32].…”

A 3d Electromechanical Fem-Based Model for Cardiac Tissue

“…For thin cardiac tissue constructs these tasks have been addressed with a device called CellDrum [24,25]. The CellDrum is a circular, 4 μm thin silicone membrane with a diameter of 16 mm.…”

“…Thus, parameters for passive and coupling models can be determined [26]. Drugs have already been applied to the culture medium leading to phenomenologically observable changes in the beating frequency, deflection, contraction duration, activation time, relaxation time and resting time [25]. Frotscher et al [14,26,27] developed an electromechanical model of the CellDrum which they parametrized, verified and validated using respective experiments.…”