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

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Jeong, Chul-Ho; Lee, Hyo-Jong; Cha, Jong-Ho; Kim, Jeong Hun; Kim, Kwang Rok; Kim, Ji-Hye; Yoon, Dae-Kwan; Kim, Kyu-Won
Issue Date
American Society for Biochemistry and Molecular Biology
J Biol Chem. 2007 May 4;282(18):13672-9. Epub 2007 Mar 14.
AnimalsCell Differentiation/drug effects/*physiologyCell Hypoxia/physiologyCell Proliferation/drug effectsEmbryonic Development/physiologyEmbryonic Stem Cells/cytology/*metabolismGene Expression Regulation, Developmental/drug effects/physiologyHypoxia-Inducible Factor 1, alphaSubunit/genetics/*metabolism/pharmacologyLeukemia Inhibitory Factor/genetics/*metabolismMiceRNA, Small Interfering/geneticsReceptors, OSM-LIF/genetics/metabolismResponse Elements/physiologySTAT3 Transcription Factor/genetics/*metabolismSignal Transduction/drug effects/*physiology
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.
0021-9258 (Print)
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College of Medicine/School of Medicine (의과대학/대학원)Ophthalmology (안과학전공)Journal Papers (저널논문_안과학전공)
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