Analyses of regulation mechanisms which induce invasion of human extravillous troophoblasts toward maternal uterine spiral arteries.

背景在人类胎盘形成过程中，胚胎来源的滋养层细胞分化为绒毛滋养层细胞和绒毛外滋养层细胞。EVTS侵入母体子宫内膜和子宫螺旋动脉的血管壁，导致子宫-胎盘循环血管阻力降低。此前，我们分析了EVT对母体子宫内膜和子宫肌层侵袭的调控机制，发现与肌层EVT相比，母体螺旋动脉周围的EVT可能保留了侵袭表型。根据这一发现，我们推测EVT可能被诱导向母体螺旋动脉侵袭，母体免疫细胞来源的因子可能是候选因素之一。结果1)体外培养的人EVT表达趋化因子受体。RT-…分析表明，培养的人EVT可表达趋化因子受体更多表达多种趋化因子受体CCR1、CCR10和XCR1。在这些趋化因子受体中，免疫组织化学分析证实CCR1在母体螺旋动脉周围的EVT上特异表达，而在子宫肌层的EVT上不表达。2)RANTES增强人EVT的侵袭性免疫组织化学分析表明，CCR1的配体之一RANTES在母体螺旋动脉周围的免疫细胞中表达。3)缺氧和蜕膜因子抑制人EVT中CCR1的表达。经Northen印迹分析，低氧条件下培养的人EVT可减弱CCR1的表达。结论母体螺旋动脉周围的氧浓度高于子宫肌层，提示母体螺旋动脉周围的EVT可能保留了CCR1的表达。由于RANTES增强了表达CCR1的人EVT的侵袭性，RANTES与CCR1的相互作用可能是诱导人EVT向母体螺旋动脉转移的因素之一。较少

BackgroundDuring human placentation, embryo-derived trophoblasts differentiate into villous trophoblasts and extravilous trophoblasts (EVT). EVTs invade into maternal endometria and vessel walls of uterine spiral arteries, which results in decreased vascular resistance of utero-placental circulation. Previously, we analyzed the mechanisms of regulated invasion of EVTs into maternal endometria and myometria, and found that EVTs around maternal spiral arteries might retain invasive phenotype compared with EVTs in myometrial layer. From this finding, we speculated that EVTs might be induced to invade toward maternal spiral arteries and factors derived from maternal immune cells might be one of candidates. Therefore in this project, we analyzed the role of maternal immune cell derived factors on the regulation mechanisms of human EVT invasion toward maternal uterine spiral arteries.Results1)Chemokine receptors are expressed in human EVTsBy RT-PCR analyses, cultured human EVTs were found to … More express various chemokine ceceptors, CCR1, CCR10 and XCR1. Among these chemokine receptors, immunohistochemical analyses confirmed that CCR1 was specifically expressed on EVTs around maternal spiral arteries but not on EVTs in myometrial layer.2) RANTES enhances the invasive property of human EVTsImmunohistochemical analyses showed that RANTES, one of ligands for CCR1, were expressed in immune cells around maternal spiral arteries. In addition, invasiveness of cultured human EVTs were enhanced in the presence of recombinant RANTES.3)Hypoxia and decidual factor attenuated CCR1 expression in human EVTsBy Northen blot analyses, culture of human EVTs in hypoxic condition attenuated the CCR1 expression. In addition, co-culture of human EVTs with maternal decidual tissue also attenuated the CCRI expression in human EVTs.ConclusionsOxygen concentration around maternal spiral arteries is higher than deep myometrial layer, which suggests that EVTs around maternal spiral arteries might retain CCR1 expression. Because RANTES enhances the invasive property of CCR1-expressing human EVTs, the interaction of RANTES and CCR1 might be one factor which induce human EVTs toward maternal spiral arteries. Less