Cardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES

Nat Commun. 2018 Jan 30;9(1):440. doi: 10.1038/s41467-017-02812-6.

Abstract

Master cell fate determinants are thought to induce specific cell lineages in gastrulation by orchestrating entire gene programs. The T-box transcription factor EOMES (eomesodermin) is crucially required for the development of the heart-yet it is equally important for endoderm specification suggesting that it may act in a context-dependent manner. Here, we define an unrecognized interplay between EOMES and the WNT signaling pathway in controlling cardiac induction by using loss and gain-of-function approaches in human embryonic stem cells. Dose-dependent EOMES induction alone can fully replace a cocktail of signaling molecules otherwise essential for the specification of cardiogenic mesoderm. Highly efficient cardiomyocyte programming by EOMES mechanistically involves autocrine activation of canonical WNT signaling via the WNT3 ligand, which necessitates a shutdown of this axis at a subsequent stage. Our findings provide insights into human germ layer induction and bear biotechnological potential for the robust production of cardiomyocytes from engineered stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cellular Reprogramming Techniques / methods*
  • Dose-Response Relationship, Drug
  • Doxycycline / administration & dosage
  • Doxycycline / pharmacology
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Human Embryonic Stem Cells / cytology
  • Humans
  • Mesoderm
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism
  • Wnt Signaling Pathway
  • Wnt3 Protein / metabolism

Substances

  • EOMES protein, human
  • T-Box Domain Proteins
  • WNT3 protein, human
  • Wnt3 Protein
  • Doxycycline