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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Hypoxia / physiology
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Cell Proliferation / drug effects
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Embryonic Development / physiology
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / metabolism*
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit / pharmacology
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Leukemia Inhibitory Factor / genetics
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Leukemia Inhibitory Factor / metabolism*
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Mice
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RNA, Small Interfering / genetics
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Receptors, OSM-LIF / genetics
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Receptors, OSM-LIF / metabolism
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Response Elements / physiology
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Leukemia Inhibitory Factor
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RNA, Small Interfering
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Receptors, OSM-LIF
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STAT3 Transcription Factor
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Stat3 protein, mouse