The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells
Jazyk angličtina Země Irsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
26723917
DOI
10.1016/j.cbi.2015.12.007
PII: S0009-2797(15)30142-3
Knihovny.cz E-zdroje
- Klíčová slova
- DMOG, Embryonic stem cells, HIF-1, Hypoxia, JNJ-42041935, Prolyl hydroxylase,
- MeSH
- aminokyseliny dikarboxylové chemie farmakologie MeSH
- benzimidazoly chemie farmakologie MeSH
- buněčná diferenciace účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- faktor 1 indukovatelný hypoxií metabolismus MeSH
- hypoxie metabolismus MeSH
- inhibitory enzymů chemie farmakologie MeSH
- kultivované buňky MeSH
- myší embryonální kmenové buňky cytologie účinky léků metabolismus MeSH
- myši MeSH
- proliferace buněk účinky léků MeSH
- prolyl-4-hydroxylasy HIF antagonisté a inhibitory metabolismus MeSH
- pyrazoly chemie farmakologie MeSH
- stabilita proteinů účinky léků MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid MeSH Prohlížeč
- aminokyseliny dikarboxylové MeSH
- benzimidazoly MeSH
- faktor 1 indukovatelný hypoxií MeSH
- inhibitory enzymů MeSH
- oxalylglycine MeSH Prohlížeč
- prolyl-4-hydroxylasy HIF MeSH
- pyrazoly MeSH
Hypoxic conditions are suggested to affect the differentiation status of stem cells (SC), including embryonic stem cells (ESC). Hypoxia inducible factor (HIF) is one of the main intracellular molecules responsible for the cellular response to hypoxia. Hypoxia stabilizes HIF by inhibiting the activity of HIF prolyl-hydroxylases (PHD), which are responsible for targeting HIF-alpha subunits for proteosomal degradation. To address the impact of HIF stabilization on the maintenance of the stemness signature of mouse ESC (mESC), we tested the influence of the inhibition of PHDs and hypoxia (1% O2 and 5% O2) on spontaneous ESC differentiation triggered by leukemia inhibitory factor withdrawal for 24 and 48 h. The widely used panhydroxylase inhibitor dimethyloxaloylglycine (DMOG) and PHD inhibitor JNJ-42041935 (JNJ) with suggested higher specificity towards PHDs were employed. Both inhibitors and both levels of hypoxia significantly increased HIF-1alpha and HIF-2alpha protein levels and HIF transcriptional activity in spontaneously differentiating mESC. This was accompanied by significant downregulation of cell proliferation manifested by the complete inhibition of DNA synthesis and partial arrest in the S phase after 48 h. Further, HIF stabilization enhanced downregulation of the expressions of some pluripotency markers (OCT-4, NANOG, ZFP-42, TNAP) in spontaneously differentiating mESC. However, at the same time, there was also a significant decrease in the expression of some genes selected as markers of cell differentiation (e.g. SOX1, BRACH T, ELF5). In conclusion, the short term stabilization of HIF mediated by the PHD inhibitors JNJ and DMOG and hypoxia did not prevent the spontaneous loss of pluripotency markers in mESC. However, it significantly downregulated the proliferation of these cells.
Citace poskytuje Crossref.org
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