Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes

• Published in: JCI insight 2018-06, Vol.3 (12)
• Main Authors: Cyganek, Lukas, Tiburcy, Malte, Sekeres, Karolina, Gerstenberg, Kathleen, Bohnenberger, Hanibal, Lenz, Christof, Henze, Sarah, Stauske, Michael, Salinas, Gabriela, Zimmermann, Wolfram-Hubertus, Hasenfuss, Gerd, Guan, Kaomei
• Format: Article
• Language: English
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.99941

Generation of homogeneous populations of subtype-specific cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSCs) and their comprehensive phenotyping is crucial for a better understanding of the subtype-related disease mechanisms and as tools for the development of chamber-specific drugs. The goals of this study were to apply a simple and efficient method for differentiation of iPSCs into defined functional CM subtypes in feeder-free conditions and to obtain a comprehensive understanding of the molecular, cell biological, and functional properties of atrial and ventricular iPSC-CMs on both the single-cell and engineered heart muscle (EHM) level. By a stage-specific activation of retinoic acid signaling in monolayer-based and well-defined culture, we showed that cardiac progenitors can be directed towards a highly homogeneous population of atrial CMs. By combining the transcriptome and proteome profiling of the iPSC-CM subtypes with functional characterizations via optical action potential and calcium imaging, and with contractile analyses in EHM, we demonstrated that atrial and ventricular iPSC-CMs and -EHM highly correspond to the atrial and ventricular heart muscle, respectively. This study provides a comprehensive understanding of the molecular and functional identities characteristic of atrial and ventricular iPSC-CMs and -EHM and supports their suitability in disease modeling and chamber-specific drug screening.