Natural Killer Cells and Hemochorial Placentation

描述(由申请人提供)：怀孕的成败在很大程度上取决于怀孕的头几周。在这些事件的过程中，建立了胎盘部位，并建立了母亲和胎儿之间的沟通水平。这一过程的基础是子宫螺旋动脉的重组。这些血管是向发育中的胎盘和胎儿输送营养的管道。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细胞。NK细胞是母体先天免疫系统的重要组成部分，在宫内胚胎着床时被招募和扩增。侵袭性绒毛外滋养层细胞是以子宫内膜，特别是子宫内膜动脉血管为靶点的滋养层细胞的特殊谱系。NK细胞和侵袭性滋养细胞的活动在时间和空间上都得到了精确的协调，以指导母胎界面的建立。这些事件的协调中断会给母亲、胎儿、新生儿和未来的成年人带来严重的后果；正如妊娠疾病中观察到的那样，先兆子痫。大鼠表现出深层的滋养层细胞侵袭和广泛的NK细胞导向和滋养层导向的子宫螺旋动脉重建；代表了一种精致的动物模型，可以从机制上深入了解妊娠的建立，包括人类血绒毛膜胎盘形成过程中发生的事件。NK细胞引导着妊娠依赖性子宫螺旋动脉重建的第一波。这些NK细胞引导的血管变化被测量并先于滋养细胞引导的子宫螺旋动脉重建。妊娠中期，NK细胞消失，侵袭性绒毛外滋养层细胞扩张，是子宫血管重塑的主要工程师。在缺乏NK细胞的情况下(通过免疫耗竭)，绒毛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细胞是母体对怀孕的基本保护性反应的指导者。NK细胞的耗竭损害了子宫螺旋动脉的发育，导致胎盘部位的缺氧，从而导致滋养细胞分化为侵袭性绒毛外滋养细胞谱系。由此可见，在血绒毛膜胎盘形成过程中，NK细胞和侵袭性绒毛外滋养细胞之间存在着动态的相互作用。我们预测，母体细胞群(NK细胞)和胚外细胞群(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。在这项研究中，我们探讨了NK细胞在绒毛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.