The NFKB Inducing Kinase Modulates Hematopoiesis During Stress
The NFKB Inducing Kinase Modulates Hematopoiesis During Stress
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DOI：
10.1002/stem.2066
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发表时间：
2015-09-01
期刊：
影响因子：
5.2
通讯作者：
Ramirez, Manuel
中科院分区：
文献类型：
--
作者：
Gonzalez-Murillo, Africa;Fernandez, Lucia;Ramirez, Manuel
在生理条件下，维持稳态期间造血的遗传程序不同于在应激期间激活的遗传程序。在这里，我们表明，造血干细胞（HSC）的替代NF B途径（NF κ B B诱导激酶，NIK，和下游分子NF κ B2）的组件的缺陷有缺陷的应激源，如超生理剂量的细胞因子，化疗和造血移植。NIK缺陷小鼠的外周血和骨髓白细胞数量在正常范围内（除了已经报道的B细胞成熟缺陷）;然而，与野生型HSC相比，HSC在体外培养中表现出明显较慢的扩增能力。这是由于细胞周期延迟和细胞凋亡增加。体内实验表明，当用清髓性化疗激发时，NIK缺陷型HSC不能以与对照相同的速度恢复。最后，NIK缺陷型HSC在体内表现出明显降低的竞争性再增殖能力。使用来自NIK的两个下游靶标之一（即NF κ B2或c-Rel）缺陷的小鼠的HSC，仅NF κ B2缺陷重现了NIK缺陷HSC检测到的缺陷。我们的研究结果强调了NIK和替代NF κ B B途径在应激后恢复正常造血水平中的作用。
The genetic programs that maintain hematopoiesis during steady state in physiologic conditions are different from those activated during stress. Here, we show that hematopoietic stem cells (HSCs) with deficiencies in components of the alternative NFjB pathway (the NF kappa B inducing kinase, NIK, and the downstream molecule NF kappa B2) had a defect in response to stressors such as supraphysiological doses of cytokines, chemotherapy, and hematopoietic transplantation. NIK-deficient mice had peripheral blood and bone marrow leukocyte numbers within normal ranges (except for the already reported defects in B-cell maturation); however, HSCs showed significantly slower expansion capacity in in vitro cultures compared to wild-type HSCs. This was due to a delayed cell cycle and increased apoptosis. In vivo experiments showed that NIK-deficient HSCs did not recover at the same pace as controls when challenged with myeloablative chemotherapy. Finally, NIK-deficient HSCs showed a significantly decreased competitive repopulation capacity in vivo. Using HSCs from mice deficient in one of two downstream targets of NIK, that is, either NFjB2 or c-Rel, only NF kappa B2 deficiency recapitulated the defects detected with NIK-deficient HSCs. Our results underscore the role of NIK and the alternative NF kappa B pathway for the recovery of normal levels of hematopoiesis after stress.