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.

Nanoantioxidants: Pioneer Types, Advantages, Limitations, and Future Insights

“…Animal experiments are complicated because of the inevitable species differences as well as ethical concerns that may prevent their use by the scientific community. Recently, some emerging non-animal models have gradually emerged for toxicity assessment, including 3D co-cultures, organoids, as well as organon-chip technologies [252][253][254]. These emerging non-animal models can simulate the structure and key functions of human organs.…”

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

“…In contrast, hiPSC technology has triggered a paradigm shift in drug discovery and clinical trials. Furthermore, hiPSCs circumvent many of the problems associated with animal and primary cell models and enable the mass production of large numbers of patient- and disease-specific CMs and other cardiac cell types [ 338 , 339 ]. The main advantage of hiPSC-derived-CMs models is that they can expand indefinitely and provide more physiologically and clinically relevant, reproducible human cell models for in vitro disease modeling and high-throughput drug screening with low cost and a limited number of animals for experiments [ 182 , 340 , 341 ].…”

Overexpression of Neuron-Derived Orphan Receptor 1 (NOR-1) Rescues Cardiomyocytes from Cell Death and Improves Viability after Doxorubicin Induced Stress

“…Furthermore, the use of a cell line (human AC16 CMs) should also be taken into consideration as cell lines do not entirely mimic primary cells [ 84 ]. However, it if difficult to maintain primary human cardiac cells in cell culture and this requires internal organ biopsy [ 85 ]. When comparing to primary cells from animal models, the AC-16 CMs provide a model that is easily genetically manipulated, yields higher biological sample volume, and, importantly, also optimal genomic specificity for translation to human applications [ 40 ].…”