title: HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress.
abstract: Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HIF1α- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2-deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1α. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2-deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoietic progenitors.
authors.affiliation: Emmy Noether Research Group, University of Technology, Dresden, Germany.
authors.forename: Rashim Pal
authors.initials: RP
authors.lastname: Singh
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.forename: Soulafa
authors.initials: S
authors.lastname: Mamlouk
authors.forename: Antje
authors.initials: A
authors.lastname: Muschter
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Gembarska
authors.forename: Tatyana
authors.initials: T
authors.lastname: Grinenko
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.forename: Stefan
authors.initials: S
authors.lastname: Bornstein
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D002454:Cell Differentiation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000502:physiology*; D051906:Smad7 Protein / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C045073:Cre recombinase; D019426:Integrases