HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress

• Published in: Blood 2013-06, Vol.121 (26), p.5158-5166
• Main Authors: Singh, Rashim Pal, Franke, Kristin, Kalucka, Joanna, Mamlouk, Soulafa, Muschter, Antje, Gembarska, Agnieszka, Grinenko, Tatyana, Willam, Carsten, Naumann, Ronald, Anastassiadis, Konstantinos, Stewart, A. Francis, Bornstein, Stefan, Chavakis, Triantafyllos, Breier, Georg, Waskow, Claudia, Wielockx, Ben
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation; Cell Cycle; Cell Differentiation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Integrases - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Procollagen-Proline Dioxygenase - physiology; Smad7 Protein - metabolism; Stress, Physiological
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-12-471185

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. • Loss of the oxygen sensor PHD2 in the HSC compartment in mice results in the HIF1α-driven induction of multipotent progenitors.• PHD2-deficient hematopoietic progenitors are outcompeted during severe stress while HSCs are encouraged to self-renew.