Natural Killer Cells and Hemochorial Placentation

自然杀伤细胞和血绒质胎盘着床

• 批准号: 9036420
• 负责人: MICHAEL J SOARES
• 金额: $ 22.42万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036420
• 关键词: Adult; Animal Model; Blood Vessels; Cell physiology; Cells; Communication; Development; Diagnostic; Disease; Dissection; Endometrial; Endometrium; Engineering; Ensure; Etiology; Event; Exhibits; Failure; Fetal Development; Fetus; Future; Genetic; Genetic Models; Health; Hemochorial Placental Development; Human; Hypoxia; Immune system; Interleukin-15; Maternal-Fetal Exchange; Measures; Modeling; Mothers; Natural Killer Cells; Newborn Infant; Nutrient; Placenta; Placenta Diseases; Placental Insufficiency; Placentation; Population; Pre-Eclampsia; Pregnancy; Process; Rattus; Recruitment Activity; Regulation; Rodent Model; Role; Site; Spiral Artery of the Endometrium; Testing; Therapeutic; Vascular remodeling; cell type; genome editing; insight; natural Blastocyst Implantation; response; success; trophoblast; zinc finger nuclease

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.

描述（由申请人提供）：怀孕的成功或失败很大程度上取决于怀孕的最初几周。在这些事件的过程中，胎盘位置被构建，母亲和胎儿之间的沟通水平也被建立。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于重塑和重新定向子宫螺旋动脉的功能至关重要：自然杀伤 (NK) 细胞和侵入性绒毛外滋养层细胞。 NK 细胞是母体先天免疫系统的重要组成部分，在子宫内胚胎植入部位被招募和扩增。侵入性绒毛外滋养层细胞代表针对子宫内膜，特别是子宫内膜动脉血管系统的特殊滋养层细胞谱系。 NK 细胞和侵袭性滋养层的活动在时间和空间上都经过精确协调，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后果；正如在妊娠疾病、先兆子痫中所观察到的那样。大鼠表现出深层滋养层浸润和广泛的 NK 细胞定向和滋养层定向子宫螺旋动脉重塑；并代表了一种精致的动物模型，用于获得妊娠建立的机制见解，包括人类血绒胎盘期间发生的事件。 NK 细胞指导第一波妊娠依赖性子宫螺旋动脉重塑。这些 NK 细胞引导的血管变化在滋养层引导的子宫螺旋动脉重塑之前进行测量。妊娠中期后，NK 细胞消失，侵入性绒毛外滋养层细胞扩张，成为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），绒毛外滋养层的侵袭和子宫螺旋动脉重塑是早熟且广泛的。因此，我们将 NK 细胞视为母体对妊娠的重要保护反应的指挥者。 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，从而导致滋养层分化转向侵入性绒毛外滋养层谱系。因此，很明显，在血绒质胎盘形成过程中，NK 细胞和侵入性绒毛外滋养层之间存在动态相互作用。我们预测，母体细胞群（NK 细胞）和胚胎外细胞群（侵入性绒毛外滋养层细胞）活动的破坏将对妊娠的成功产生影响。在本提案中，我们探讨了 NK 细胞在血绒胎盘和妊娠相关疾病中的作用。