Natural Killer Cells and Hemochorial Placentation

描述（由申请人提供）：怀孕的成功或失败在很大程度上取决于怀孕的第一周。在这些事件的过程中，胎盘形成部位被构建，母亲和胎儿之间的交流水平被建立。这一过程的基础是子宫螺旋动脉的重建。这些血管是将营养物质输送到发育中的胎盘和胎儿的管道。两种关键细胞类型对重塑和重定向子宫螺旋动脉的功能至关重要：自然杀伤（NK）细胞和侵袭性绒毛外滋养层细胞。NK细胞是母体先天免疫系统的组成部分，并在子宫内胚胎植入部位募集和扩增。侵袭性绒毛外滋养层细胞代表了一种专门的滋养层细胞谱系，靶向子宫内膜，特别是子宫内膜动脉血管系统。NK细胞和浸润性滋养层细胞的活动在时间和空间上都是精确协调的，以指导母胎界面的建立。这些事件的协调中断会对母亲、胎儿、新生儿和未来的成年人造成严重后果;如在妊娠疾病先兆子痫中所观察到的。大鼠表现出深层滋养层浸润和广泛的NK细胞导向和滋养层导向的子宫螺旋动脉重塑;并代表了一个精致的动物模型，用于获得建立妊娠的机制见解，包括人类血绒膜胎盘形成期间发生的事件。NK细胞引导妊娠依赖性子宫螺旋动脉重构的第一波。测量这些NK细胞引导的血管变化，并先于滋养层引导的子宫螺旋动脉重塑。妊娠中期后，NK细胞消失，浸润性绒毛外滋养层细胞扩张，并代表子宫血管重塑的主要工程师。在缺乏NK细胞（通过免疫耗竭）的情况下，绒毛外滋养层细胞的侵袭和子宫螺旋动脉重塑是早熟和广泛的。因此，我们认为NK细胞作为董事的一个重要的母体保护性反应怀孕。NK细胞的耗竭损害子宫螺旋动脉发育，导致胎盘形成部位缺氧，这导致滋养层分化重定向为侵袭性绒毛外滋养层谱系。因此，很明显，在血绒膜胎盘形成过程中，NK细胞和侵袭性绒毛外滋养层细胞之间存在动态的相互作用。我们预测，这种母体细胞群（NK细胞）和这种胚外细胞群（侵袭性绒毛外滋养层细胞）的活动中断将对妊娠的成功产生影响。在本研究中，我们探讨了NK细胞在血绒膜胎盘形成和妊娠相关疾病中的作用。

DESCRIPTION (provided by applicant): The success or failure of a pregnancy is largely determined during the first weeks of pregnancy. In the course of these events the placentation site is constructed and the level of communication between mother and fetus established. Fundamental to this process is the restructuring of uterine spiral arteries. These blood vessels are the conduit that delivers nutrients to the developing placenta and fetus. Two key cell types are pivotal to reshaping and redirecting the function of the uterine spiral arteries: natural kille (NK) cells and invasive extravillous trophoblast cells. NK cells are an integral component of the maternal innate immune system and are recruited and expanded at the site of intrauterine embryo implantation. Invasive extravillous trophoblast cells represent a specialized lineage of trophoblast cells targeted to the endometrium, especially the endometrial arterial vasculature. The activities of NK cells and invasive trophoblast are precisely orchestrated, both temporally and spatially, to guide establishment of the maternal-fetal interface. Disruptions in the coordination of these events results in severe consequences to mother, fetus, newborn, and future adult; as observed in the pregnancy disease, preeclampsia. The rat exhibits deep trophoblast invasion and extensive NK cell-directed and trophoblast-directed uterine spiral artery remodeling; and represents an exquisite animal model for gaining mechanistic insights into the establishment of pregnancy, including events transpiring during human hemochorial placentation. NK cells direct the first wave of pregnancy-dependent uterine spiral artery remodeling. These NK cell-guided vascular changes are measured and precede trophoblast-directed uterine spiral artery remodeling. After midgestation NK cells disappear and invasive extravillous trophoblast cells expand and represent the primary engineers of uterine vascular remodeling. In the absence of NK cells (via immunodepletion), invasion of extravillous trophoblast and uterine spiral artery remodeling are precocious and extensive. We therefore view NK cells as directors of an essential maternal protective response to pregnancy. Depletion of NK cells impairs uterine spiral artery development leading to hypoxia at the placentation site, which results in the redirection of trophoblast differentiation to the invasive extravillous trophoblast lineage. Thus it is apparent that there is a dynamic interplay between NK cells and invasive extravillous trophoblast during hemochorial placentation. We predict that disruptions in the activities of this maternal cell population (NK cells) and this extraembryonic cell population (invasive extravillous trophoblast cells) will have consequences on the success of pregnancy. In this proposal we explore the role of NK cells in hemochorial placentation and pregnancy-related diseases.