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

Roberto Quaranta, Jakob Fell, Frank Ruhle, Jyoti Rao, Ilaria Piccini, Marcos J. Arauzo-Brave, Arie O. Verkerk, Monika Stoll, Boris Greber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Web of Science)

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.
Original languageEnglish
Article numbere31706
Number of pages23
JournalElife
Volume7
DOIs
Publication statusPublished - 16 Jan 2018

Keywords

  • PLURIPOTENT STEM-CELLS
  • IN-VITRO MATURATION
  • CARDIOVASCULAR PROGENITORS
  • CARDIAC DEVELOPMENT
  • LIMB DEVELOPMENT
  • MAMMALIAN HEART
  • REGULATING ISL1
  • SMOOTH-MUSCLE
  • DIFFERENTIATION
  • CARDIOMYOCYTES

Cite this