BINÓ, Lucia, Jan KUČERA, Kateřina ŠTEFKOVÁ, Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ, Martina LÁNOVÁ, Jana KUDOVÁ, Lukáš KUBALA and Jiří PACHERNÍK. The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells. Chemico-Biological Interactions. Clare: Elsevier Ireland Ltd., 2016, vol. 244, January, p. 204-214. ISSN 0009-2797. Available from: https://dx.doi.org/10.1016/j.cbi.2015.12.007.
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Basic information
Original name The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells
Authors BINÓ, Lucia (703 Slovakia, belonging to the institution), Jan KUČERA (203 Czech Republic, belonging to the institution), Kateřina ŠTEFKOVÁ (203 Czech Republic, belonging to the institution), Lenka ŠVIHÁLKOVÁ ŠINDLEROVÁ (203 Czech Republic), Martina LÁNOVÁ (203 Czech Republic, belonging to the institution), Jana KUDOVÁ (203 Czech Republic, belonging to the institution), Lukáš KUBALA (203 Czech Republic, guarantor) and Jiří PACHERNÍK (203 Czech Republic, belonging to the institution).
Edition Chemico-Biological Interactions, Clare, Elsevier Ireland Ltd. 2016, 0009-2797.
Other information
Original language English
Type of outcome Article in a journal
Field of Study Genetics and molecular biology
Country of publisher Ireland
Confidentiality degree is not subject to a state or trade secret
Impact factor Impact factor: 3.143
RIV identification code RIV/00216224:14310/16:00089311
Organization unit Faculty of Science
Doi http://dx.doi.org/10.1016/j.cbi.2015.12.007
UT WoS 000369152000022
Keywords in English DMOG; Embryonic stem cells; HIF-1; Hypoxia; JNJ-42041935; Prolyl hydroxylase
Tags AKR, EL OK, podil, rivok
Tags International impact, Reviewed
Changed by Changed by: Ing. Andrea Mikešková, učo 137293. Changed: 14/4/2017 15:40.
Abstract
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.
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