Jenkins Brendan J, Quilici Cathy, Roberts Andrew W, Grail Dianne, Dunn Ashley R, Ernst Matthias
Ludwig Institute for Cancer Research, Molecular Biology Laboratory, Victoria, Australia.
Exp Hematol. 2002 Nov;30(11):1248-56. doi: 10.1016/s0301-472x(02)00929-3.
Studies on mice lacking the common receptor subunit gp130 reveal that activation of gp130-dependent signaling pathways is essential for normal fetal and adult hematopoiesis. However, the extent to which hematopoiesis is dependent upon activation of a particular gp130 signaling pathway, namely STAT1/3 or SHP2/MAPK, is unknown. This study examined the specific contribution of gp130-mediated STAT1/3 signaling to the regulation of hematopoiesis.
Hematopoiesis was examined at various developmental stages in mice homozygous for a targeted carboxy-terminal truncation mutation in gp130 (gp130(delta)/(delta)) that deletes all STAT1/3 binding sites, thereby abolishing gp130-mediated STAT1/3 activation.
Adult gp130(delta)/(delta) mice have increased numbers of immature colony-forming unit spleen progenitor cells in the bone marrow and spleen, elevated numbers of committed myeloid progenitor cells in the spleen and peripheral blood, and leukocytosis. Increased progenitor cell production was observed in gp130(delta)/(delta) fetal livers from 14 days of gestation onward. In contrast, the circulating platelet count was reduced by 30% in gp130(delta)/(delta) mice, without any corresponding decrease in the number of bone marrow and splenic megakaryocytes. In liquid cultures, megakaryocytes from gp130(delta)/(delta) mice are smaller than those from wild-type mice and do not increase in size upon stimulation with interleukin-6 or interleukin-11. Administration of either interleukin-6 or interleukin-11 to gp130(delta)/(delta) mice failed to increase platelet numbers, despite an increase in the production of megakaryocytes.
Collectively, these results reveal that gp130-mediated STAT1/3 activation is required to maintain the normal balance of hematopoietic progenitors during fetal and adult hematopoiesis. Furthermore, they suggest two distinct roles for gp130-mediated STAT1/3 activation in hematopoiesis, one restricting the production of immature hematopoietic progenitor cells and the other promoting the functional maturation of megakaryocytes to produce platelets.
对缺乏共同受体亚基gp130的小鼠进行的研究表明，gp130依赖性信号通路的激活对于正常的胎儿和成人造血至关重要。然而，造血在多大程度上依赖于特定的gp130信号通路（即STAT1/3或SHP2/MAPK）的激活尚不清楚。本研究探讨了gp130介导的STAT1/3信号传导对造血调节的具体作用。
在gp130基因发生靶向羧基末端截短突变（gp130(δ)/(δ)）的纯合小鼠的不同发育阶段检测造血情况，该突变删除了所有STAT1/3结合位点，从而消除了gp130介导的STAT1/3激活。
成年gp130(δ)/(δ)小鼠骨髓和脾脏中未成熟的集落形成单位脾祖细胞数量增加，脾脏和外周血中定向髓系祖细胞数量升高，且出现白细胞增多。从妊娠14天起，在gp130(δ)/(δ)胎肝中观察到祖细胞生成增加。相比之下，gp130(δ)/(δ)小鼠的循环血小板计数降低了30%，而骨髓和脾脏中的巨核细胞数量没有相应减少。在液体培养中，gp130(δ)/(δ)小鼠的巨核细胞比野生型小鼠的小，并且在用白细胞介素-6或白细胞介素-11刺激后大小不会增加。给gp130(δ)/(δ)小鼠注射白细胞介素-6或白细胞介素-11均未能增加血小板数量，尽管巨核细胞生成有所增加。
总体而言，这些结果表明，gp130介导的STAT1/3激活是维持胎儿和成人造血过程中造血祖细胞正常平衡所必需的。此外，它们提示了gp130介导的STAT1/3激活在造血中的两个不同作用，一个是限制未成熟造血祖细胞的产生，另一个是促进巨核细胞的功能成熟以产生血小板。
