Modeling heart disease in a dish: From somatic cells to disease-relevant cardiomyocytes

Abstract

A scientific milestone that has tremendously impacted the cardiac research field has been the discovery and establishment of human-induced pluripotent stem cells (hiPSC). Key to this discovery has been uncovering a viable path in generating human patient and disease-specific cardiac cells to dynamically model and study human cardiac diseases in an in vitro setting. Recent studies have demonstrated that hiPSC-derived cardiomyocytes can be used to model and recapitulate various known disease features in hearts of patient donors harboring genetic-based cardiac diseases. Experimental drugs have also been tested in this setting and shown to alleviate disease phenotypes in hiPSC-derived cardiomyocytes, further paving the way for therapeutic interventions for cardiac disease. Here, we review state-of-the-art methods to generate high-quality hiPSC and differentiate them towards cardiomyocytes as well as the full range of genetic-based cardiac diseases, which have been modeled using hiPSC. We also provide future perspectives on exploiting the potential of hiPSC to compliment existing studies and gain new insights into the mechanisms underlying cardiac disease.

Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems

“…These interactions may also contribute to human cardiac disease settings, where defects in myocyte-fibroblast coupling may underlie cardiac fibrosis and arrhythmias, which are highly prevalent. Given the increasing number of hiPSC-based models of cardiac disease [129] and the advent of 3D engineered tissue models using hiPSCs [130], future studies focused on better understanding the impact of myocyte-fibroblast communication in these 2D and 3D model systems would be of significant interest to better understand their contribution to human disease settings.…”

Organ-on-a-chip platforms for studying drug delivery systems

“…Most of the developed platforms use primary cells derived from rats, however, more focus on integration of human cells with these models is required for mimicking human physiological response. Among the human cell sources, cardiomyocytes generated from human induced pluripotent stem cells have enormous potential to be pathophysiologically relevant [77]. They also facilitate creation of platforms for mimicking genetic disorder in patient-specific cases, thereby paving the way for individualized therapy [77].…”

Patient-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization of Cardiac Cells

“…Similar to human embryonic stem cells, hiPSCs have the potential to differentiate into virtually any cell type in the human body, offering enticing possibilities to study organ- and system-specific disorders, including diseases affecting the heart (1). Additionally, hiPSC-derived cardiomyocytes constitute a robust platform for the assessment of cardiotoxicity, a major contributor to the failure of potential novel drugs in later stages of clinical trials (2).…”

“…Several genetic diseases bearing cardiac phenotypes have been modeled with hiPSCs including LEOPARD syndrome (3), long QT syndrome (4–7), Timothy syndrome (8), catecholaminergic polymorphic ventricular tachycardia (9–12), familial dilated (13) and hypertrophic cardiomyopathies (14, 15), arrhythmogenic right ventricular cardiomyopathy (16–18), as well as an overlapping syndrome of a cardiac Na + channel disease (19). As the field has evolved, several differentiation protocols have been developed for the differentiation of hiPSCs toward the cardiac lineages (1). Currently, the most popular protocols rely on small-molecule-mediated temporal modulation of the Wnt pathway (20, 21).…”