The cholinergic system is involved in regulation of the development of the hematopoietic system.
The cholinergic system is involved in regulation of the development of the hematopoietic system.
复制标题
DOI：
10.1016/j.lfs.2007.04.017
复制
发表时间：
2007-05
期刊：
影响因子：
6.1
通讯作者：
Naira Serobyan;S. Jagannathan;I. Orlovskaya;I. Schraufstatter;M. Skok;J. Loring;S. Khaldoyanidi
中科院分区：
文献类型：
--
作者：
Naira Serobyan;S. Jagannathan;I. Orlovskaya;I. Schraufstatter;M. Skok;J. Loring;S. Khaldoyanidi
基因表达谱显示，胆碱能系统的组成部分，包括胆碱乙酰转移酶、乙酰胆碱酯酶和烟碱型乙酰胆碱受体(NAChRs)在胚胎干细胞和分化胚体(EBS)中表达。尼古丁激活EBS中nAChRs的表达，导致MAPK的激活和自发分化向血管母细胞转移。在体内，非神经性的nAChRs在胚胎发育的早期就被检测到，这些nAChRs位于胎儿的造血部位。同样，在体内将发育中的胚胎暴露于尼古丁会导致胎肝中造血祖细胞的数量增加。然而，产后造血干/祖细胞(HSPC)数量减少，提示HSPC在胎儿骨髓中的定植受到损害。这与循环HSPC数量增加和CXCR4表达减少有关，CXCR4介导循环细胞迁移到骨髓调节缝隙。此外，蛋白质微阵列显示，尼古丁改变了在利基中产生的细胞因子的特征。IL-1α、IL-1β、IL-2、IL-9、IL-10水平无明显变化，而G-CSF、GM-CSF、IL-3、IL-6、IGFBP-3等造血支持细胞因子的产生减少。这与HSPC在体内的再生能力降低以及尼古丁处理的骨髓培养中的造血活性减弱有关。有趣的是，尼古丁刺激IL4和IL5的产生，暗示胆碱能系统可能在变态反应性疾病的发病机制中发挥作用。我们的数据证明，尼古丁在妊娠期引起的胆碱能系统失衡干扰了正常发育，并为主动吸烟者和被动吸烟者产后产生负面健康后果提供了基础。
Gene expression profiling demonstrated that components of the cholinergic system, including choline acetyltransferase, acetylcholinesterase and nicotinic acetylcholine receptors (nAChRs), are expressed in embryonic stem cells and differentiating embryoid bodies (EBs). Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast. In vivo, non-neural nAChRs are detected early during development in fetal sites of hematopoiesis. Similarly, in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver. However postpartum, the number of hematopoietic stem/progenitor cells (HSPC) was decreased, suggesting an impaired colonization of the fetal bone marrow with HSPCs. This correlated with increased number of circulating HSPC and decreased expression of CXCR4 that mediates migration of circulating cells into the bone marrow regulatory niche. In addition, protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche. While the levels of IL1α, IL1β, IL2, IL9 and IL10 were not changed, the production of hematopoiesis-supportive cytokines including G-CSF, GM-CSF, IL3, IL6 and IGFBP-3 was decreased. This correlated with the decreased repopulating ability of HSPC in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine. Interestingly, nicotine stimulated the production of IL4 and IL5, implying a possible role of the cholinergic system in pathogenesis of allergic diseases. Our data provide evidence that the nicotine-induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers.