Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation
Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation
复制标题
DOI：
10.1038/leu.2010.97
复制
发表时间：
2010-07-01
期刊：
影响因子：
11.4
通讯作者：
Askenasy, N.
中科院分区：
文献类型：
--
作者：
Mizrahi, K.;Stein, J.;Askenasy, N.
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）信号通路对恶性肿瘤细胞具有选择性毒性。TRAIL受体DR 4和DR 5在人脐带血细胞中以低水平（3-15%）表达，并且通过与同源配体孵育而上调，从而在70-80%的受体阳性细胞中触发凋亡（P < 0.001）。造血祖细胞中不诱导凋亡，这是由持续的严重联合免疫缺陷重建潜力和克隆形成活性确定的。此外，与TRAIL孵育72小时后死亡细胞的消除导致骨髓祖细胞的三倍富集。在半固体培养物中暴露于TRAIL显示了DR 4和粒细胞/巨噬细胞集落刺激因子在招募谱系阴性（lin（-））和CD 34（+）祖细胞以及促进大集落形成方面的协同活性。在鼠骨髓中，类似于30%的lin（-）细胞表达TRAIL-R2（唯一的鼠受体），并且受体在移植后在归巢到宿主骨髓的循环和分化供体细胞中上调。然而，该受体几乎在最原始的（lin（-）SCA-1（+）c-kit（+））祖细胞中普遍表达，并刺激lin（-）细胞的克隆形成活性（P < 0.001），表明移植后的嗜性功能。可以得出结论，TRAIL不会触发造血祖细胞的凋亡，并且在应激条件下其同源受体的上调介导支持从发育不全恢复的嗜性信号传导。白血病（2010）24，1325-1334; doi：10.1038/leu.2010.97;在线发表于2010年5月20日
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway has selective toxicity to malignant cells. The TRAIL receptors DR4 and DR5 are expressed at low levels in human umbilical cord blood cells (3-15%) and are upregulated by incubation with the cognate ligand, triggering apoptosis in 70-80% of receptor-positive cells (P < 0.001). Apoptosis is not induced in hematopoietic progenitors, as determined from sustained severe combined immunodeficiency reconstituting potential and clonogenic activity. Furthermore, elimination of dead cells after incubation with TRAIL for 72 h results in a threefold enrichment in myeloid progenitors. Exposure to TRAIL in semisolid cultures showed synergistic activity of DR4 and granulocyte/macrophage colony-stimulating factor in recruiting lineage-negative (lin(-)) and CD34(+) progenitors and in promoting the formation of large colonies. In murine bone marrow, similar to 30% of lin(-) cells express TRAIL-R2 (the only murine receptor), and the receptor is upregulated after transplantation in cycling and differentiating donor cells that home to the host marrow. However, this receptor is almost ubiquitously expressed in the most primitive (lin(-)SCA-1(+)c-kit(+)) progenitors, and stimulates the clonogenic activity of lin(-) cells (P < 0.001), suggesting a tropic function after transplantation. It is concluded that TRAIL does not trigger apoptosis in hematopoietic progenitors, and upregulation of its cognate receptors under stress conditions mediates tropic signaling that supports recovery from hypoplasia. Leukemia (2010) 24, 1325-1334; doi:10.1038/leu.2010.97; published online 20 May 2010