title: 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.
abstract: 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.
authors.affiliation: Neurovascular Coordination Research Center, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Jeong
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Cha
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Kwang Rok
authors.initials: KR
authors.lastname: Kim
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Dae-Kwan
authors.initials: DK
authors.lastname: Yoon
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D047108:Embryonic Development / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053605:Leukemia Inhibitory Factor; D034741:RNA, Small Interfering; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse