Revised roles of ISL1 in a hES cell-based model of human heart chamber specification

eLife

Jyoti Rao¹  Arie O Verkerk¹  Boris Greber¹  Jakob Fell¹  Ilaria Piccini²  Frank Rühle³  Monika Stoll³  Roberto Quaranta³  Marcos J Araúzo-Bravo³ 

[1] Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany;Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany;Human Stem Cell Pluripotency Laboratory, Max Planck Institute for Molecular Biomedicine, Münster, Germany;

关键词: human embryonic stem cells;    directed cardiac differentiation;    cardiac subtype specification;    Islet-1;   

DOI  :  10.7554/eLife.31706

来源: DOAJ

【 摘 要 】

The transcription factor ISL1 is thought to be key for conveying the multipotent and proliferative properties of cardiac precursor cells. Here, we investigate its function upon cardiac induction of human embryonic stem cells. We find that ISL1 does not stabilize the transient cardiac precursor cell state but rather serves to accelerate cardiomyocyte differentiation. Conversely, ISL1 depletion delays cardiac differentiation and respecifies nascent cardiomyocytes from a ventricular to an atrial identity. Mechanistic analyses integrate this unrecognized anti-atrial function of ISL1 with known and newly identified atrial inducers. In this revised view, ISL1 is antagonized by retinoic acid signaling via a novel player, MEIS2. Conversely, ISL1 competes with the retinoic acid pathway for prospective cardiomyocyte fate, which converges on the atrial specifier NR2F1. This study reveals a core regulatory network putatively controlling human heart chamber formation and also bears implications for the subtype-specific production of human cardiomyocytes with enhanced functional properties.

【 授权许可】

Unknown