A Cardiac Cell Outgrowth Assay for Evaluating Drug Compounds Using a Cardiac Spheroid-on-a-Chip Device.

Jonas Christoffersson,Michelle Coffee,Robert Zweigerdt,Carl-Fredrik Mandenius,Florian Meier,Henning Kempf,Mario Beilmann,Kristin Schwanke

doi:10.3390/bioengineering5020036

Jonas Christoffersson, Michelle Coffee + Show 6 more

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https://doi.org/10.3390/bioengineering5020036

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Abstract

Three-dimensional (3D) models with cells arranged in clusters or spheroids have emerged as valuable tools to improve physiological relevance in drug screening. One of the challenges with cells cultured in 3D, especially for high-throughput applications, is to quickly and non-invasively assess the cellular state in vitro. In this article, we show that the number of cells growing out from human induced pluripotent stem cell (hiPSC)-derived cardiac spheroids can be quantified to serve as an indicator of a drug’s effect on spheroids captured in a microfluidic device. Combining this spheroid-on-a-chip with confocal high content imaging reveals easily accessible, quantitative outgrowth data. We found that effects on outgrowing cell numbers correlate to the concentrations of relevant pharmacological compounds and could thus serve as a practical readout to monitor drug effects. Here, we demonstrate the potential of this semi-high-throughput “cardiac cell outgrowth assay” with six compounds at three concentrations applied to spheroids for 48 h. The image-based readout complements end-point assays or may be used as a non-invasive assay for quality control during long-term culture.

Highlights

The recent development of perfused three-dimensional (3D) cell culture models, or organs-on-chip, offers the possibility to investigate biological responses of chemicals and pharmaceuticals in a model that better mimics the in vivo cell environment than conventional two-dimensional culture models [1,2]
We show that the number of cells growing out from human induced pluripotent stem cell-derived cardiac spheroids can be quantified to serve as an indicator of a drug’s effect on spheroids captured in a microfluidic device
During routine culture of cardiac spheroids on laminin coated surfaces, we observed that some cardiac cells tended to grow out from the aggregates and attach to the surrounding surface

Summary

Introduction

The recent development of perfused three-dimensional (3D) cell culture models, or organs-on-chip, offers the possibility to investigate biological responses of chemicals and pharmaceuticals in a model that better mimics the in vivo cell environment than conventional two-dimensional culture models [1,2]. Results from such assays are believed to increase the predictivity of drug effects on human tissue such as efficacy and toxicity. Compared to conventional static conditions, dynamic cell cultures have been shown to have positive effects on several cell types [15,16,17] and to support functional outputs of cardiac aggregates [18]

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