Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency

Nat Commun. 2015 May 13;6:7095. doi: 10.1038/ncomms8095.

Abstract

Leukemia inhibitory factor (LIF)/STAT3 signalling is a hallmark of naive pluripotency in rodent pluripotent stem cells (PSCs), whereas fibroblast growth factor (FGF)-2 and activin/nodal signalling is required to sustain self-renewal of human PSCs in a condition referred to as the primed state. It is unknown why LIF/STAT3 signalling alone fails to sustain pluripotency in human PSCs. Here we show that the forced expression of the hormone-dependent STAT3-ER (ER, ligand-binding domain of the human oestrogen receptor) in combination with 2i/LIF and tamoxifen allows human PSCs to escape from the primed state and enter a state characterized by the activation of STAT3 target genes and long-term self-renewal in FGF2- and feeder-free conditions. These cells acquire growth properties, a gene expression profile and an epigenetic landscape closer to those described in mouse naive PSCs. Together, these results show that temporarily increasing STAT3 activity is sufficient to reprogramme human PSCs to naive-like pluripotent cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / physiology*
  • Feeder Cells
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation / physiology*
  • Humans
  • Leukemia Inhibitory Factor / genetics
  • Leukemia Inhibitory Factor / metabolism
  • Mice
  • Pluripotent Stem Cells / physiology*
  • Protein Array Analysis
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Tamoxifen / pharmacology

Substances

  • LIF protein, human
  • Leukemia Inhibitory Factor
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tamoxifen
  • Fibroblast Growth Factor 2