Hypoxia-inducible factor-1 alpha inhibits self-renewal of mouse embryonic stem cells in Vitro via negative regulation of the leukemia inhibitory factor-STAT3 pathway

J Biol Chem. 2007 May 4;282(18):13672-9. doi: 10.1074/jbc.M700534200. Epub 2007 Mar 14.


During mammalian embryogenesis, the early embryo grows in a relatively hypoxic environment due to a restricted supply of oxygen. The molecular mechanisms underlying modulation of self-renewal and differentiation of mouse embryonic stem cells (mESCs) under such hypoxic conditions remain to be established. Here, we show that hypoxia inhibits mESC self-renewal and induces early differentiation in vitro, even in the presence of leukemia inhibitory factor (LIF). These effects are mediated by down-regulation of the LIF-STAT3 signaling pathway. Under conditions of hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter. Ectopic expression and small interference RNA knockdown of HIF-1alpha verified the inhibitory effect on LIFR transcription. Our findings collectively suggest that hypoxia-induced in vitro differentiation of mESCs is triggered, at least in part, by the HIF-1alpha-mediated suppression of LIF-STAT3 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Hypoxia / physiology
  • Cell Proliferation / drug effects
  • Embryonic Development / physiology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / pharmacology
  • Leukemia Inhibitory Factor / genetics
  • Leukemia Inhibitory Factor / metabolism*
  • Mice
  • RNA, Small Interfering / genetics
  • Receptors, OSM-LIF / genetics
  • Receptors, OSM-LIF / metabolism
  • Response Elements / physiology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Leukemia Inhibitory Factor
  • RNA, Small Interfering
  • Receptors, OSM-LIF
  • STAT3 Transcription Factor
  • Stat3 protein, mouse