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

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, Trian; Breier, Georg; Waskow, Claudia; Wielockx, Ben

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

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Franke, Kristin
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Kalucka, Joanna
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

Mamlouk, Soulafa
Max Planck Society;

Muschter, Antje
Max Planck Society;

Gembarska, Agnieszka
Max Planck Society;

/persons/resource/persons219480

Naumann, Ronald
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

Anastassiadis, Konstantinos
Max Planck Society;

Bornstein, Stefan
Max Planck Society;

Chavakis, Trian
Max Planck Society;

Breier, Georg
Max Planck Society;

Waskow, Claudia
Max Planck Society;

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引用

Singh, R. P., Franke, K., Kalucka, J., Mamlouk, S., Muschter, A., Gembarska, A., Grinenko, T., Willam, C., Naumann, R., Anastassiadis, K., Stewart, A. F., Bornstein, S., Chavakis, T., Breier, G., Waskow, C., & Wielockx, B. (2013). HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. Blood, 121(26), 5158-5166.

引用: https://hdl.handle.net/21.11116/0000-0001-06E4-7

要旨

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.