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最初几周。在这些过程中，胎盘位置被构建，母亲和胎儿之间的交流水平被建立。这个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。两种关键细胞类型是重塑和重定向子宫螺旋动脉功能的关键：自然杀伤（NK）细胞和浸润性滋养细胞。NK细胞是母体先天免疫系统的一个组成部分，在宫内胚胎着床时被募集和扩增。浸润性外滋养细胞是一种以子宫内膜，尤其是子宫内膜动脉血管为靶点的特殊滋养细胞。NK细胞和侵袭性滋养细胞的活动在时间和空间上都被精确地安排，以指导母胎界面的建立。这些事件协调的中断会对母亲、胎儿、新生儿和未来的成年人造成严重后果；如在妊娠期观察到的疾病，子痫前期。大鼠表现出深层滋养细胞侵袭和广泛的NK细胞定向和滋养细胞定向子宫螺旋动脉重构；并代表了一个精致的动物模型，以获得怀孕的建立机制的见解，包括在人类血液胎盘过程中发生的事件。NK细胞引导妊娠依赖性子宫螺旋动脉重构的第一波。这些NK细胞引导的血管变化是在滋养细胞引导的子宫螺旋动脉重塑之前测量的。妊娠中期后，NK细胞消失，浸润性滋养细胞扩张，是子宫血管重构的主要工程师。在缺乏NK细胞的情况下（通过免疫缺失），上皮外滋养细胞的侵袭和子宫螺旋动脉重构是早熟和广泛的。因此，我们认为NK细胞是孕妇对怀孕的基本保护反应的主管。NK细胞的耗竭会损害子宫螺旋动脉的发育，导致胎盘部位缺氧，从而导致滋养细胞分化向浸润性外滋养细胞谱系转移。因此，在血液胎盘形成过程中，NK细胞和浸润性滋养细胞之间明显存在动态的相互作用。我们预测，母体细胞群（NK细胞）和胚胎外细胞群（侵入性外滋养细胞）活动的中断将对怀孕的成功产生影响。在本提案中，我们探讨NK细胞在血液胎盘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.