title: Adult hematopoietic stem cells lacking Hif-1α self-renew normally.
abstract: The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance.
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Catarina
authors.initials: C
authors.lastname: Sepulveda
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Chithra
authors.initials: C
authors.lastname: Subramani
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Amélie V
authors.initials: AV
authors.lastname: Guitart
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Jasmine
authors.initials: J
authors.lastname: Mohr
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Lewis
authors.initials: L
authors.lastname: Allen
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Theano I
authors.initials: TI
authors.lastname: Panagopoulou
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Jasmin
authors.initials: J
authors.lastname: Paris
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Hannah
authors.initials: H
authors.lastname: Lawson
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Villacreces
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Alejandro
authors.initials: A
authors.lastname: Armesilla-Diaz
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom; Klinik fuer Haematologie, Onkologie und Stammzelltransplantation, Universitaetsklinikum Aachen, Aachen, Germany; Paul O'Gorman Leukaemia Research Centre, Institute for Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors.forename: Deniz
authors.initials: D
authors.lastname: Gezer
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Institute for Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; and.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;
authors.forename: Kamil R
authors.initials: KR
authors.lastname: Kranc
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002455:Cell Division / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit