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

2018; American Society for Clinical Investigation; Volume: 3; Issue: 12 Linguagem: Inglês

10.1172/jci.insight.99941

2379-3708

Lukas Cyganek, Malte Tiburcy, Karolina Sekeres, Kathleen Gerstenberg, Hanibal Bohnenberger, Christof Lenz, Sarah Henze, Michael Stauske, Gabriela Salinas, Wolfram‐Hubertus Zimmermann, Gerd Hasenfuß, Kaomei Guan,

Tissue Engineering and Regenerative Medicine

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.