Cellular Atlas of the Human Placenta: Structure-Function Relationships and their Implications for Placental Dysfunction

人类胎盘细胞图谱：结构-功能关系及其对胎盘功能障碍的影响

基本信息

批准号：
10657738
负责人：
Mana M Parast
金额：
$ 58.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657738
关键词：
Address Affect Atlases Basal Plate Biological Models Blood Vessels Cells Chorionic villi Clinical Data Decidua Deposition Development Disease Evaluation Extracellular Matrix Fetal Growth Retardation Fibrin Functional disorder Gases Gene Expression Heterogeneity Histopathology Human Injury Interferons Lesion Maintenance Mass Spectrum Analysis Maternal-Fetal Exchange Modeling Molecular Molecular Analysis Molecular Profiling Morphology Nutrient Organ Paracrine Communication Pathologic Pathologist Phenotype Placenta Placenta Diseases Pre-Eclampsia Pregnancy Proliferating RNA Regenerative capacity Reproducibility Role Signal Transduction Structure-Activity Relationship Syncytiotrophoblast Testing Thrombosis Tissues Validation Vascular Endothelial Cell Villous cell injury cell type cytotrophoblast digital experimental study fetal fetal loss in vitro Model neonatal outcome new technology prenatal regeneration potential response self-renewal stem stem cells transcriptome sequencing trophoblast

项目摘要

Project Summary/Abstract Little is known about structure-function relationships in the human placenta. As pathologists, we can view the placenta only after delivery, and correlate our findings to clinical and prenatal course, as well as neonatal outcome. At best, however, we have lesions which correlate with disease, but have yet to be validated, either directly, through molecular analysis, or indirectly, through manipulation and functional analysis of in vitro models. Placental dysfunction, manifested clinically as preeclampsia (PE) with or without fetal growth restriction (FGR), is associated with histopathologic lesions of maternal vascular malperfusion (MVM) and fetal vascular malperfusion (FVM). These lesions differentially affect the three trophoblast compartments: cytotrophoblast (CTB, the putative stem cell), syncytiotrophoblast (STB, the cell type responsible for gas/nutrient exchange), and extravillous trophoblast (EVT, the invasive cell type at the maternal-fetal interface). Nevertheless, our understanding of these lesions is limited to morphology and immunolocalization of a few markers. Over the past few years, multiple groups, including ours, have used scRNAseq to characterize cellular heterogeneity within both normal and diseased placentae; however, these studies remain mostly descriptive, lacking both spatial context of the molecular data and functional evaluation of the distinct cell types. We therefore propose to apply novel technologies, including digital spatial profiling (DSP) and tissue decellularization followed by extracellular matrix (ECM)-specific mass spectrometry, as discovery-based approaches to better characterize specific MVM and FVM lesions at the molecular level. We will then use primary term CTB, to reproducibly model these phenotypes and to perform functional validation as part of a targeted evaluation approach. We will test the hypothesis that late gestation CTB respond to specific cell- and ECM-derived signals to proliferate and/or differentiate into either STB or EVT, thus identifying potential regenerative capacity in this unique transient organ. We will also probe the cellular and ECM origins of PE-associated placental dysfunction, testing the hypothesis that this disease originates from alterations in ECM composition and paracrine signaling from both placental and decidual (maternal) cells. Successful completion of this proposal will establish a detailed cellular and matrix atlas of the human placenta, with validated structure-function relationships, laying the groundwork for probing placental regenerative capacity in the setting of placental dysfunction.

项目摘要/摘要关于人胎盘中的结构功能关系知之甚少。作为病理学家，我们可以查看只有在分娩后胎盘，并将我们的发现与临床和产前过程以及新生儿结果。但是，充其量，我们的病变与疾病有关，但尚未直接通过分子分析或间接验证，通过操纵和功能验证分析体外模型。胎盘功能障碍，在临床上表现为先兆子痫（PE），没有胎儿生长限制（FGR），与母体血管的组织病理病变有关厌食症（MVM）和胎儿血管疏松率（FVM）。这些病变差异影响三个滋养细胞室：细胞增生层细胞（CTB，推定的干细胞），合成型植物细胞（STB，负责气/营养交换的细胞类型）和牙周滋养细胞（EVT，侵入性细胞类型在母亲界面上）。然而，我们对这些病变的理解仅限于形态和一些标记的免疫定位。在过去的几年中，包括我们的多个小组使用scrnaseq表征正常和患病胎盘内的细胞异质性；但是，这些研究仍然主要是描述性的，缺乏分子数据的空间背景和不同细胞类型的功能评估。因此，我们建议采用新技术，包括数字空间分析（DSP）和组织脱细胞化，然后是细胞外基质（ECM）特异性质谱法，作为基于发现的方法，以更好地表征特定的MVM和FVM病变在分子水平。然后，我们将使用原始术语CTB，可重复地对这些表型进行建模和作为目标评估方法的一部分，执行功能验证。我们将检验以下假设晚期妊娠CTB对特定的细胞和ECM衍生的信号反应，以增殖和/或分化为/或 STB或EVT，因此可以识别此独特的瞬态器官中的潜在再生能力。我们还将探测PE相关胎盘功能障碍的细胞和ECM起源，测试假设该疾病源于ECM组成和旁分泌信号的改变胎盘和dec骨（母体）细胞既是成功完成此建议将建立一个人胎盘的详细细胞和基质图集，具有验证的结构功能关系，为探测胎盘再生能力的基础胎盘功能障碍。