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

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...

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Published ineLife Vol. 7
Main Authors Quaranta, Roberto, Fell, Jakob, Rühle, Frank, Rao, Jyoti, Piccini, Ilaria, Araúzo-Bravo, Marcos J, Verkerk, Arie O, Stoll, Monika, Greber, Boris
Format Journal Article
LanguageEnglish
Published England eLife Science Publications, Ltd 16.01.2018
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects
Analysis
cardiac subtype specification
Cardiomyocytes
CRISPR
Developmental Biology
directed cardiac differentiation
Embryo cells
Embryonic stem cells
Experiments
Fate
Gene expression
Genetic engineering
Genomics
Heart
Heart cells
Heart diseases
human embryonic stem cells
Identity
Islet-1
Islet-1 protein
Novels
Proteins
Research centers
Retinoic acid
Rodents
Stem cells
Transcription factors
Tretinoin
Ventricle
Amsterdam Netherlands
Germany
Islet-1
stem cells
developmental biology
cardiac subtype specification
human
directed cardiac differentiation
human embryonic stem cells
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Summary: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.
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RheinCell Therapeutics GmbH, Langenfeld, Germany.
Department of Genetics, Harvard Medical School and Brigham and Women’s Hospital, Boston, United States.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.31706