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

Roberto Quaranta,Boris Greber,Jakob Fell,Arie O Verkerk,Jyoti Rao,Frank Rühle,Ilaria Piccini,Marcos J Araúzo-Bravo,Monika Stoll

doi:10.7554/elife.31706

Abstract

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.

Highlights

The four chambers of the mammalian heart are specified from the first and second heart fields (FHF/ SHF) encompassing distinct precursor cell populations that give rise, respectively, to the left ventricle (FHF) and the mostly SHF-derived right ventricle, left and right atria, and outflow tract (Buckingham et al, 2005)
Given its key role in vertebrate cardiogenesis and its implication in the cardiac precursor cell state, we sought to investigate the function of ISL1 upon cardiac induction of human ES cells
At day 5, the approximate peak expression time point of ISL1 in this protocol (Rao et al, 2016), ISL1 was undetectable in KO cells, as expected (Figure 1C)

Summary

Introduction

The four chambers of the mammalian heart are specified from the first and second heart fields (FHF/ SHF) encompassing distinct precursor cell populations that give rise, respectively, to the left ventricle (FHF) and the mostly SHF-derived right ventricle, left and right atria, and outflow tract (Buckingham et al, 2005). The LIM domain transcription factor ISL1 (Islet-1) is a prime player in and marker of the SHF from which, both ventricular and atrial cells originate (Cai et al, 2003). The view that the SHF gives rise to the right ventricle and outflow tract, and to most cells of the atria, is a result of revised lineage-tracing experiments in the mouse embryo using improved Isl1-Cre driver lines (in Yang et al, 2006).

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Conclusion