Characterization of Cell-Subpopulations in the preeclamptic placenta and decidua

子痫前期（PE）是一种妊娠疾病，表现为血压突然升高，并伴有蛋白尿。肺动脉栓塞是导致产妇和胎儿发病和死亡的主要原因，也是晚年罹患心血管疾病的危险因素。总体而言，全世界所有怀孕中有5-10%会发生PE。胎盘是一个独特的临时器官，它为胎儿充当肺、肝、肠、肾和内分泌腺，为胎儿提供营养和氧气，并协调胎儿和母亲免疫系统之间的串扰。母胎界面的结构特点是胎儿细胞和母体组织之间的复杂关系，功能障碍会对母亲和孩子造成严重后果。在细胞水平上理解胎盘生物学是至关重要的，随着新的单细胞测序技术的发展，这一点现在成为可能。单细胞测序通过优化的下一代测序（NGS）技术检测来自单个细胞的序列信息。这项技术的发展导致了人类细胞图谱（HCA）计划的建立，该计划旨在在单细胞水平上创建整个生物体组织图谱。在之前的拨款HE6249/7-1中，我们获得了“妊娠早期胎盘中滋养细胞亚群的表征”的资助。在DFG的帮助下，我们能够分析妊娠早期的绒毛和蜕膜，现在可以展示妊娠早期子宫胎盘单元的细胞图。在此更新提案中，我们申请资助“通过单细胞测序表征子痫前期胎盘和蜕膜中的细胞亚群”。我们将研究来自对照组和子痫前期胎盘和蜕膜的细胞，并将结果与妊娠早期样本的数据结合起来。这种方法将给见解在发展过程中的胎盘和机制导致子痫前期。我们的总体假设是，与正常妊娠相比，子痫前期子宫胎盘单位的细胞亚群存在错误分化过程。为了实现我们的目标，我们将利用一些新的计算方法：聚类技术，基于本体的分子特征推断，基因调控网络的重建，空间细胞定位，连续细胞周期分析和综合单细胞方法。具体来说，我们将追求以下目标：目标1：细胞亚群分析将揭示子痫前期和控制性胎盘/蜕膜之间的差异；目标2：假时间分析将揭示妊娠早期和足月胎盘/蜕膜之间的分化过程，并在子痫前期受到干扰。

Preeclampsia (PE) is a pregnancy disorder manifested by a sudden increase in blood pressure, accompanied by a Proteinuria. PE is the leading cause of maternal and fetal morbidity and mortality and a risk factor for developing cardiovascular diseases in later life. Overall, 5-10% of all pregnancies worldwide develop PE. The placenta is a unique temporary organ, which acts as lungs, liver, gut, kidneys and endocrine glands for the fetus, supplying it with nutrients and oxygen, and harmonizes the cross-talk between the fetal and maternal immune system. The structure of the maternal-fetal interface Features a complex relationship between fetal cells and maternal tissue and dysfunctions causes severe consequence for mother and child. It is essential to understand placenta biology on a cellular level, which is now possible with the development of new promising single-cell sequencing technology. Single cell sequencing examines the sequence information from individual cells with optimized next generation sequencing (NGS) technologies. The development of this technology led to the construction of the Human Cell Atlas (HCA) initiative, which aims to create whole-organism tissue maps at the single-cell level. With the previous grant HE6249/7-1 we were fundedfor the “Characterization of Trophoblast-Subpopulations in first trimester placenta”. With the help of the DFG we were able to analyze first trimester villi and decidua and now can present a cell map of the uteroplacental unit in the first trimester of pregnancy. Within thisrenewal proposal here, we apply for funding for the “Characterization of Cell-Subpopulations in the preeclamptic placenta and decidua” by single cell sequencing. We will investigate cells from control and preeclamptic placenta and decidua and will combine the results withthe data from the first trimester samples. This approach will give insights in the developing process of the placenta and in mechanisms leading to preeclampsia. Our global hypothesis is that the cell subpopulations underlie a faulty differentiation process in thepreeclamptic uteroplacental unit compared to uneventful pregnancies. To achieve our goal we will utilize number of novel computational methods: clustering techniques, ontology based molecular signature inference, reconstruction of gene regulatory networks, spatial cell localization, continuum cell cycle analysis and integrative single-cell methods. Specifically, we will pursue the following objectives: Objective 1: Cell sub-populations analysis will reveal differences between the preeclamptic and control placenta/decidua Objective 2:Pseudotime analysis will reveal differentiation processes between the first trimester and term placenta/decidua and are disturbed in preeclampsia.