Trophoblast-Uterine Cell Dynamics at the Maternal-Fetal Interface

母胎界面是子宫和胎盘结构协同促进胎儿发育的动态部位。大鼠、小鼠和人各有一个血绒膜胎盘。滋养层细胞是胎盘的实质细胞，并且具有分化成专门的细胞类型的能力，包括表现出具有进入脉管系统和重构子宫螺旋动脉的潜力的侵入性特性的细胞。在人类中，这些侵入性滋养层细胞被称为绒毛外滋养层细胞。滋养细胞入侵和滋养细胞定向的子宫螺旋重塑的破坏是“大产科综合征”的核心，包括早期妊娠丢失、先兆子痫、宫内生长受限和早产。 血绒膜胎盘有不同的形态，这影响了研究滋养层细胞侵袭和子宫螺旋动脉重塑的动物模型的适用性。与小鼠相反，大鼠表现出血绒膜胎盘形成，子宫内滋养层细胞侵入较深，这一特征也在人类胎盘形成中观察到。大鼠可以有效地用于测试侵入性/绒毛外滋养层细胞发育的假定调节因子的生理相关性。 我们研究的长期目标是确定侵袭性/绒毛外滋养层细胞发育和侵袭性滋养层/绒毛外滋养层引导的子宫螺旋动脉重塑的保守调节因子。我们将使用单细胞RNA测序（RNA-seq）和转座酶可降解染色质测序试验（ATAC-seq）对大鼠妊娠期间从子宫-胎盘界面分离的细胞群进行分析。测序数据将通过稳健的计算分析进行查询，并与为人类子宫-胎盘界面内的细胞生成的现有数据集整合。这项任务最好是通过协调努力的专家对大鼠胎盘和计算分析的滋养层转录。该实验将提供侵袭性滋养层/绒毛外滋养层细胞发育和滋养层引导的子宫螺旋动脉重塑的候选保守调节因子的强大列表，用于未来的分析。此外，我们将获得对子宫-胎盘界面其他基本成分的新见解，包括免疫，内皮，基质和平滑肌细胞，这些细胞对怀孕的健康和成功有重要贡献。从调查中获得的见解将推动未来的分析使用管道的功能丧失和功能获得的方法在人类滋养层干细胞和基因操纵的大鼠模型。

The maternal-fetal interface is a dynamic site where uterine and placental structures cooperate to promote development of the fetus. The rat, mouse, and human each possess a hemochorial placenta. Trophoblast cells are the parenchymal cells of the placenta and have the capacity to differentiate into specialized cell types, including cells that exhibit invasive properties with the potential to enter the vasculature and restructure uterine spiral arteries. In the human, these invasive trophoblast cells are referred to as extra villous trophoblast cells. Disruptions of trophoblast invasion and trophoblast-directed uterine spiral remodeling are centerpieces of the “Great Obstetrical Syndromes”, including early pregnancy loss, preeclampsia, intrauterine growth restriction, and pre-term birth. The hemochorial placenta comes in different forms, which impact the suitability of animal models for investigating trophoblast cell invasion and uterine spiral artery remodeling. In contrast to the mouse, the rat exhibits hemochorial placentation with deep intrauterine trophoblast cell invasion, a feature also observed in human placentation. The rat can be effectively used to test the physiological relevance of putative regulators of invasive/extra villous trophoblast cell development. The long-term goal of our research is to identify conserved regulators of invasive/extra villous trophoblast cell development and invasive trophoblast/extra villous trophoblast-guided uterine spiral artery remodeling. We will use single-cell RNA-sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin-sequencing (ATAC-seq) of cell populations isolated from the uterine-placental interface through gestation of the rat. Sequencing data will be interrogated through robust computational analyses and integrated with existing datasets generated for cells within the human uterine-placental interface. This task is best accomplished through the coordinated efforts of experts on rat placentation and computational analysis of the trophoblast transcriptome. The experimentation will provide a robust list of candidate-conserved regulators of invasive trophoblast/extra villous trophoblast cell development and trophoblast-guided uterine spiral artery remodeling for future analysis. Furthermore, we will gain new insights into other essential constituents of the uterine- placental interface, including immune, endothelial, stromal, and smooth muscle cells, which importantly contribute to the health and success of pregnancy. The insights gained from the investigation will fuel future analyses using a pipeline of loss-of-function and gain-of-function approaches in human trophoblast stem cells and genetically manipulated rat models.