Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation

Forristal, Catherine E., Winkler, Ingrid G., Nowlan, Bianca, Barbier, Valerie, Walkinshaw, Gail and Levesque, Jean-Pierre (2013) Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation. Blood, 121 5: 759-769. doi:10.1182/blood-2012-02-408419


Author Forristal, Catherine E.
Winkler, Ingrid G.
Nowlan, Bianca
Barbier, Valerie
Walkinshaw, Gail
Levesque, Jean-Pierre
Total Author Count Override 6
Title Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2013-01-31
Year available 2012
Sub-type Article (original research)
DOI 10.1182/blood-2012-02-408419
Open Access Status Not yet assessed
Volume 121
Issue 5
Start page 759
End page 769
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Collection year 2013
Language eng
Formatted abstract
Quiescent hematopoietic stem cells (HSCs) preferentially reside in poorly perfused niches that may be relatively hypoxic. Most of the cellular effects of hypoxia are mediated by O2-labile hypoxia-inducible transcription factors (HIFs). To investigate the effects of hypoxia on HSCs, we blocked O2-dependent HIF-1α degradation in vivo in mice by injecting 2 structurally unrelated prolyl hydroxylase domain (PHD) enzyme inhibitors: dimethyloxalyl glycine and FG-4497. Injection of either of these 2 PHD inhibitors stabilized HIF-1α protein expression in the BM. In vivo stabilization of HIF-1α with these PHD inhibitors increased the proportion of phenotypic HSCs and immature hematopoietic progenitor cells in phase G0 of the cell cycle and decreased their proliferation as measured by 5-bromo-2′-deoxyuridine incorporation. This effect was independent of erythropoietin, the expression of which was increased in response to PHD inhibitors. Finally, pretreatment of mice with a HIF-1α stabilizer before severe, sublethal 9.0-Gy irradiation improved blood recovery and enhanced 89-fold HSC survival in the BM of irradiated mice as measured in long-term competitive repopulation assays. The results of the present study demonstrate that the levels of HIF-1α protein can be manipulated pharmacologically in vivo to increase HSC quiescence and recovery from irradiation.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print December 14, 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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