Multilevel defects in the hematopoietic niche in essential thrombocythemia
Multilevel defects in the hematopoietic niche in essential thrombocythemia
复制标题
原发性血小板增多症造血生态位的多级缺陷
DOI：
10.3324/haematol.2018.213686
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发表时间：
2020-03-01
期刊：
影响因子：
10.1
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
--
作者：
Sun, Ting;Ju, Mankai;Zhang, Lei
骨髓小生境在原发性血小板增多症（ET）中的作用尚不清楚。在这里，我们观察到JAK 2 V617 F阳性ET患者的造血生态位存在多层次缺陷，包括间充质基质细胞（MSC）功能缺陷、免疫失衡和交感神经损伤。JAK 2 V617 F阳性原发性血小板增多症患者的间充质基质细胞具有转化的转录组。同时，它们表现出增殖增强，凋亡和衰老减少，分化成脂肪细胞和骨细胞的能力减弱，以及对正常造血的支持不足。此外，它们在抑制免疫反应方面效率低下。例如，它们对CD 4阳性T细胞的增殖和活化以及炎性因子可溶性CD 40配体的分泌的抑制作用很差。它们也很少诱导免疫抑制性T辅助2细胞（Th 2）的形成和抗炎因子白细胞介素-4（IL-4）的分泌。此外，我们确定WDR 4是一种低表达的有效蛋白，与JAK 2 V617 F阳性ET患者MSC中增殖增加、衰老和分化减少以及正常造血支持不足相关。基于我们的体外研究，我们还观察到MSC细胞中WDR 4的缺失通过ERK-GSK 3 β-CREB信号转导下调白细胞介素-6（IL-6）水平。总之，我们的研究结果表明，JAK 2 V617 F阳性ET患者的骨髓生态位发生多层次的变化，MSC中WDR 4的低表达可能是诱导造血相关变化的关键。
The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, including functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced proliferation, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosuppressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased proliferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK–GSK3β–CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.