HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress.
HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress.
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DOI：
10.1182/blood-2012-12-471185
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发表时间：
2013-06
期刊：
影响因子：
20.3
通讯作者：
R. Singh;K. Franke;Joanna Kalucka;S. Mamlouk;A. Muschter;Agnieszka Gembarska;T. Grinenko;C. Willam;R. Naumann;K. Anastassiadis;K. Anastassiadis;A. F. Stewart;S. Bornstein;T. Chavakis;G. Breier;Claudia Waskow;B. Wielockx
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文献类型：
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作者：
R. Singh;K. Franke;Joanna Kalucka;S. Mamlouk;A. Muschter;Agnieszka Gembarska;T. Grinenko;C. Willam;R. Naumann;K. Anastassiadis;K. Anastassiadis;A. F. Stewart;S. Bornstein;T. Chavakis;G. Breier;Claudia Waskow;B. Wielockx
缺氧是维持造血干细胞（HSC）静止和多能性的一个显著特征。缺氧诱导因子（HIF）脯氨酰羟化酶结构域蛋白（PHDs）作为氧传感器，因此可以调节这一系统。在这里，我们描述了一种小鼠品系，其在非常早期的造血前体中具有HIF脯氨酰羟化酶2（PHD2）的条件性缺失，这导致多能祖细胞在稳态条件下以HIF 1 α和SMAD7依赖的方式自我更新。竞争性骨髓（BM）移植显示PHD 2缺陷细胞的外周和中央嵌合体减少，但最原始的祖细胞没有。相反，在整个BM转移中，PHD2缺陷型HSC补充整个造血系统，并显示出依赖于HIF 1 α的增强的自我更新能力。两者合计，我们的研究结果表明，PHD2的损失控制在生理条件下的HSC隔室的维护，并导致PHD2缺陷型造血细胞的竞争力在应激过程中由它们的野生型对应物，同时促进非常早期的造血祖细胞的自我更新。
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.