Cells 2021, 10, 3483. https://doi.org/10.3390/cells10123483 www.mdpi.com/journal/cells Review Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective Mohamed M. Bekhite * and P. Christian Schulze Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, 07747 Jena, Germany; Christian.Schulze@med.uni-jena.de * Correspondence: Mohamed.el_Saied@med.uni-jena.de; Tel.: +49-3641-9325-813 Abstract: A comprehensive understanding of the pathophysiology and cellular responses to drugs in human heart disease is limited by species differences between humans and experimental animals. In addition, isolation of human cardiomyocytes (CMs) is complicated because cells obtained by bi- opsy do not proliferate to provide sufficient numbers of cells for preclinical studies in vitro. Inter- estingly, the discovery of human-induced pluripotent stem cell (hiPSC) has opened up the possibil- ity of generating and studying heart disease in a culture dish. The combination of reprogramming and genome editing technologies to generate a broad spectrum of human heart diseases in vitro offers a great opportunity to elucidate gene function and mechanisms. However, to exploit the po- tential applications of hiPSC-derived-CMs for drug testing and studying adult-onset cardiac dis- ease, a full functional characterization of maturation and metabolic traits is required. In this review, we focus on methods to reprogram somatic cells into hiPSC and the solutions for overcome imma- turity of the hiPSC-derived-CMs to mimic the structure and physiological properties of the adult human CMs to accurately model disease and test drug safety. Finally, we discuss how to improve the culture, differentiation, and purification of CMs to obtain sufficient numbers of desired types of hiPSC-derived-CMs for disease modeling and drug development platform. Keywords: iPSC; cardiomyocytes; metabolic phenotype; genome-editing; disease modeling; drug testing 1. Introduction Many cardiac diseases are characterized by functional and structural abnormalities that lead to myocyte death [1,2]. To this end, several in vivo and in vitro models have been established to investigate environmental factors for cardiomyopathies such as myocardi- tis, cardiotoxicity, and non-ischemic as well as genetic cardiomyopathies [3–8]. However, the lack of knowledge about the underlying causes and mechanisms of cardiomyopathy has been recognized. Therefore, a better understanding of the pathogenic mechanisms is crucial to capture the early stages of disease development and to develop sensitive and effective drugs with fewer side effects. Due to difficulties in obtaining human adult car- diomyocytes (CMs), primary cell lines (neonatal CMs and adult CMs) from rodent hearts [9,10], immortalized cell lines (H9C2) [11], ANT-T antigen [12], AT-1 cells [13], MC29 [14], HL -1 [15], and AC16 [16], as well as mice and rats have provided the model for basic research and pharmaceutical investigation of human heart disease [5,6]. However, pri- mary cell lines and immortalized cell lines may have genetic and metabolic abnormalities due to their origin, resulting in misleading cellular responses to pathological stress. In addition, some cases of human genetic cardiomyopathies, such as the Tmem43 (Trans- membrane protein 43) mutation in the nuclear lamina-associated protein genes, which causes arrhythmogenic cardiomyopathy (ACM) in several families, cannot be modeled Citation: Bekhite, M.M.; Schulze, P.C. Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective. Cells 2021, 10, 3483. https://doi.org/ 10.3390/cells10123483 Academic Editor: Andrea Pession Received: 5 November 2021 Accepted: 6 December 2021 Published: 9 December 2021 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2021 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (http://crea- tivecommons.org/licenses/by/4.0/).