title: Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation.
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-1a 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.
  
  
  CONCLUSIONS
  HIF-1α protein stabilization increases HSC quiescence in vivo. HIF-1α protein stabilization increases HSC resistance to irradiation and accelerates recovery.
authors.affiliation: Stem Cell Biology Group, Mater Medical Research Institute, South Brisbane, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Forristal
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.forename: Bianca
authors.initials: B
authors.lastname: Nowlan
authors.forename: Valerie
authors.initials: V
authors.lastname: Barbier
authors.forename: Gail
authors.initials: G
authors.lastname: Walkinshaw
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004921:Erythropoietin / Q000096:biosynthesis; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects / Q000528:radiation effects*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000600:Amino Acids, Dicarboxylic; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011480:Protease Inhibitors; D004921:Erythropoietin; C040947:oxalylglycine