Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function
Deletion of the NF-κB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function
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DOI：
10.1182/blood-2013-02-486142
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发表时间：
2013-06-20
期刊：
影响因子：
20.3
通讯作者：
Baldwin, Albert S.
中科院分区：
文献类型：
--
作者：
Stein, Sarah J.;Baldwin, Albert S.
造血是一个严格控制的过程，导致血细胞的产生。造血干细胞(HSCs)的自我更新和分化是造血发育的关键过程。这些步骤的中断可能导致细胞分布的改变和疾病。为了研究核因子-kappa B亚单位relA/p65在体内调节HSCs中的作用，我们建立了在造血室中缺乏rela/p65的小鼠。使用这个模型系统，我们发现P65的丢失严重损害了HSC的功能，并且伴随着造血干和造血祖细胞周期的增加、髓外造血和分化缺陷。表型HSC的基因芯片研究表明，在谱系受限的细胞中正常表达的基因上调，以及参与HSC维持和动态平衡的基因下调。我们假设，p65缺陷细胞中基因表达的变化导致造血干细胞和祖细胞的自我更新和分化效率降低。这些研究表明，p65是一种重要的造血调节因子，它通过转录与HSC命运相关的基因来实现。
Hematopoiesis is a tightly regulated process resulting in the production of blood cells. Self-renewal and differentiation of hematopoietic stem cells (HSCs) are key processes in hematopoietic development. Disruption of these steps can lead to altered cell distribution and disease. To investigate the role of the nuclear factor-kappa B subunit RelA/p65 in the regulation of HSCs in vivo, we generated mice lacking RelA/p65 in the hematopoietic compartment. Using this model system, we show that loss of p65 severely impairs HSC function and occurs in conjunction with increased hematopoietic stem and progenitor cell cycling, extramedullary hematopoiesis, and differentiation defects. Gene array studies of phenotypic HSCs indicate the up-regulation of genes normally expressed in lineage restricted cells, as well as the down-regulation of genes involved in HSC maintenance and homeostasis. We hypothesize that changes in gene expression in p65-deficient cells lead to decreased self-renewal and differentiation efficiency of hematopoietic stem and progenitor cells. These studies demonstrate that p65 is an important regulator of hematopoiesis through the transcription of genes involved in HSC fate.