Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

Abstract

Development of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.

Keywords: 3D structures; Body-on-a-chip; Cardiomyocytes; Cardiotoxicity; Drug research; EHT; Engineered heart tissue; Heart-on-a-chip; Organoids; Spheroids; Stem cells; hiPSC; hiPSC-CMs.

Fig. 1

Main advantages and limitations of available cellular models based on cardiomyocytes and other cell types present in heart for the use in cardiotoxicity studies and new drug development

Fig. 2

The most common tools for evaluation of drug effects in hiPSC-CM-based in vitro models

Fig. 3

hiPSC-derived cardiomyocytes growing in a a spheroid (cells were immunofluorescently stained for troponin I (red) and actin (green); nuclei were stained with 4′6-diamidino-2-phenylindole (DAPI)) and in b co-culture with hiPSC-derived endothelial cells within ibidi μ-slide after 24 h of shear stress (cells were immunofluorescently stained for troponin I (green) (a marker of cardiomyocytes) and VE-cadherin (red) (a marker of endothelial cells); nuclei were stained with DAPI)

Fig. 4

Methods of 3D hiPSC-CM-based structure formation