Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies

Abstract

In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

“…The heart is a complex tissue consisting of multiple cell types, yet the bulk of the volume of the heart is comprised of cardiomyocytes Pinto et al, 2016), which are particularly susceptible to oxygen deprivation given their high metabolic activity. iPSC-derived cardiomyocytes (iPSC-CMs) have been shown to be a useful model for studying genetic effects on various cardiovascular traits and diseases, as well for studying gene regulation (Banovich et al, 2018;Benaglio et al, 2019;Brodehl et al, 2019;Burridge et al, 2016;de la Roche et al, 2019;Ma et al, 2018;McDermott-Roe et al, 2019;Panopoulos et al, 2017;Pavlovic et al, 2018;Ward and Gilad, 2019).…”

RNA-Based Strategies for Cardiac Reprogramming of Human Mesenchymal Stromal Cells

“…Further, they can overcome certain limitations that have been attributed to PSCs, including ESC and iPSC. In contrast to ESC, MSC do not provoke any ethical concerns [12,37,38]. Moreover, pre-clinical studies demonstrated a tumorigenic potential of ESC and iPSC-derived cell products that has not been observed for MSC to date [42][43][44][45].…”

“…In vitro generated cardiomyocytes are an important tool for cardiovascular research, as they can be utilized for disease modelling or for the development of drug screening assays to assess the cardiac toxic risk of established or newly synthesized drugs [37][38][39]. Moreover, promising preclinical data suggests the therapeutic potential of generated cardiomyocytes for the treatment of cardiac diseases to overall improve heart regeneration and function [40,41].…”

Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects

“…Indeed, CRISPR/Cas9 has been zealously received by cell biologists as an attractive tool for SC research [203]. In cardiovascular biology, CRISPR/Cas9 was successfully applied to patient-derived iPSC to target disease-causing mutations of CVDs [204][205][206]. A recent study demonstrated the utility of CRISPR/Cas9 in phenotypic characterization of iPSC-CMs from patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) [207].…”