HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α.
HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α.
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作者：
许多血液肿瘤患者不能动员足够数量的造血干细胞（HSC），以响应粒细胞集落刺激因子（G-CSF），排除随后的自体HSC移植。Plerixafor是趋化因子受体CXCR 4的特异性拮抗剂，可以挽救部分但不是所有单独使用G-CSF动员失败的患者。这些难治性动员不良者目前不能从自体移植中获益。为了发现增强HSC动员的替代靶向途径，我们研究了缺氧诱导因子-1 α（HIF-1α）的作用以及HIF-1α药理学稳定化对小鼠HSC动员的影响。我们在HSC特异性条件性缺失Hif 1a基因的小鼠中证明，氧不稳定转录因子HIF-1α对G-CSF和普乐沙福引起的HSC动员至关重要。相反，与目前临床上使用的最有效的动员组合G-CSF+普乐沙福相比，使用4-脯氨酰羟化酶抑制剂FG-4497对HIF-1α进行药理学稳定与G-CSF和普乐沙福协同作用，使重建HSC的动员增加20倍。
Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic.
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影响因子：
20.3
作者：
Forristal, Catherine E.;Winkler, Ingrid G.;Levesque, Jean-Pierre
通讯作者：
Levesque, Jean-Pierre
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Göthert, JR;Gustin, SE;Begley, CG
通讯作者：
Begley, CG
DOI：
10.1007/978-1-61779-943-3_11
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Barbier, Valerie;Winkler, Ingrid G;Levesque, Jean-Pierre
通讯作者：
Levesque, Jean-Pierre
影响因子：
64.5
作者：
Frenette, PS;Mayadas, TN;Wagner, DD
通讯作者：
Wagner, DD