Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor
Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor
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DOI：
10.1111/j.1365-2141.2005.05580.x
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发表时间：
2005-07-01
影响因子：
6.5
通讯作者：
Jiang, XH
中科院分区：
文献类型：
--
作者：
Arcasoy, MO;Jiang, XH
针对与失血或溶血相关的贫血，循环红细胞的再生涉及红细胞生成速率的增加和原红细胞的扩增，原红细胞是最终分化为成熟红细胞的骨髓前体细胞。本研究探讨了促红细胞生成素（Epo）和干细胞因子（Scf）调节原成红细胞扩增的机制。在CD 34（+）细胞的液体培养物中产生了原代人原成红细胞的同源群体。在无血清培养中，proerythroblasts未能生存在Epo或Scf单独存在下，但表现出协同增殖反应的联合Epo和Scf治疗，表现出一个对数扩增在5天。Epo和Scf引起的细胞内信号转导表明，非受体酪氨酸激酶Janus激酶2（Jak 2）的下游靶点信号转导子和转录激活子（Stat）5的酪氨酸磷酸化由Epo介导，而不是Scf。促分裂原活化蛋白激酶（MAPK）细胞外调节激酶（Erk）1-2在Epo或Scf的作用下磷酸化。磷酸化Akt，磷脂酰肌醇3-激酶（PI 3 K）下游的信号分子，观察到以下Scf，但不是Epo治疗。为了确定特定信号传导途径对响应Epo和Scf的协同作用的原成红细胞协同扩增的贡献，用靶向Jak 2、PI 3 K和MAPK激酶的激酶抑制剂处理细胞。有一个显着的，剂量依赖性抑制原成红细胞扩增的反应，所有三种激酶抑制剂。总之，Epo和Scf介导的初级红系前体细胞的合作、协同扩增需要选择性激活多种信号传导途径，包括Jak-Stat、PI 3 K和MAPK途径。
The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34(+) cells. In serum-free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one-log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non-receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1-2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3-kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co-operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose-dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo- and Scf-mediated co-operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak-Stat, PI3K and MAPK pathways.