Xiu Yan, Xue Wingel Y, Lambertz Allyn, Leidinger Mariah, Gibson-Corley Katherine, Zhao Chen
Department of Pathology Carver College of Medicine, University of Iowa, IA, USA.
West High School, Iowa City, IA, USA.
Stem Cells. 2017 Mar;35(3):777-786. doi: 10.1002/stem.2523. Epub 2016 Nov 2.
Previously we have shown that loss of non-canonical NF-κB signaling impairs self-renewal of hematopoietic stem/progenitor cells (HSPCs). This prompted us to investigate whether persistent activation of the non-canonical NF-κB signaling will have supportive effects on HSPC self-renewal. NF-κB-inducing kinase (NIK) is an important kinase that mainly activates the non-canonical pathway through directly phosphorylating IKKα. In contrast to our expectations, constitutive activation of NIK in the hematopoietic system leads to bone marrow (BM) failure and postnatal lethality due to intrinsic impairment of HSPC self-renewal and extrinsic disruption of BM microenvironment through enhancing osteoclastogenesis. The impaired HSPC function is associated with reduced cell proliferation and increased apoptosis and inflammatory cytokine responses. RNAseq analysis of control and NIK-activated HSPCs reveals that these effects are through non-canonical NF-κB signaling without significant changes in the canonical pathway. Gene set expression analysis of RNAseq data reveals globally decreased stem cell signature, increased maturation signature, and increased inflammatory responses. Many genes (Mpl, Tifab, Emcn, Flt3, Bcl2, and others) that regulate HSPC self-renewal, lineage commitment, and apoptosis are significantly downregulated-and those genes that regulate inflammatory responses and cell cycle inhibition (Cdkn2a and Cdkn2b) are significantly upregulated-by activation of NIK. Importantly, our data demonstrate that activation of NIK-non-canonical signaling has distinct phenotypes-smaller spleen size, decreased white blood cell counts, and reduced HSPC proliferation-compared to activation of canonical signaling. Collectively, these data indicate that the balanced non-canonical NF-κB signaling is essential for maintaining normal hematopoiesis and NIK-non-canonical signaling contributes to the development of BM failure. Stem Cells 2017;35:777-786.
此前我们已经表明，非经典NF-κB信号通路的缺失会损害造血干/祖细胞（HSPCs）的自我更新能力。这促使我们研究非经典NF-κB信号通路的持续激活是否会对HSPC自我更新产生支持作用。NF-κB诱导激酶（NIK）是一种重要的激酶，主要通过直接磷酸化IKKα来激活非经典通路。与我们的预期相反，造血系统中NIK的组成性激活会导致骨髓（BM）衰竭和出生后死亡，这是由于HSPC自我更新的内在损伤以及通过增强破骨细胞生成对BM微环境的外在破坏所致。HSPC功能受损与细胞增殖减少、细胞凋亡增加以及炎症细胞因子反应增强有关。对对照和NIK激活的HSPC进行RNAseq分析表明，这些效应是通过非经典NF-κB信号通路产生的，而经典通路没有显著变化。对RNAseq数据进行基因集表达分析发现，干细胞特征总体下降，成熟特征增加，炎症反应增强。许多调节HSPC自我更新、谱系定向和细胞凋亡的基因（Mpl、Tifab、Emcn、Flt3、Bcl2等）被显著下调，而那些调节炎症反应和细胞周期抑制的基因（Cdkn2a和Cdkn2b）则因NIK的激活而显著上调。重要的是，我们的数据表明，与经典信号通路激活相比，NIK非经典信号通路激活具有不同的表型——脾脏尺寸较小、白细胞计数减少以及HSPC增殖减少。总体而言，这些数据表明，平衡的非经典NF-κB信号通路对于维持正常造血至关重要，而NIK非经典信号通路则导致BM衰竭的发生。《干细胞》2017年；35:777 - 786。
