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

• 批准号: 10367204
• 负责人: Mana M Parast
• 金额: $ 52.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10367204
• 关键词: Address; Affect; Atlases; Basal Plate; Biological Models; Blood Vessels; Cells; Chorion; Chorionic villi; Clinical; Cytoskeleton; Data; Decidua; Deposition; Development; Disease; Endothelial Cells; 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; Role; Signal Transduction; Structure-Activity Relationship; Syncytiotrophoblast; Testing; Thrombosis; Tissues; Validation; Villous; base; 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

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.

项目总结/摘要 对人类胎盘的结构-功能关系知之甚少。作为病理学家，我们可以看到 胎盘只有在分娩后，并将我们的研究结果与临床和产前过程，以及 新生儿结局最好的情况下，然而，我们有与疾病相关的病变，但还没有被发现。 通过分子分析直接验证，或通过操作和功能分析间接验证。 体外模型分析。胎盘功能障碍，临床表现为先兆子痫（PE）， 无胎儿生长受限（FGR），与母体血管的组织病理学病变相关 灌注不良（MVM）和胎儿血管灌注不良（FVM）。这些病变对这三种疾病的影响不同。 滋养层区室：细胞滋养层（CTB，假定的干细胞），合胞体滋养层（STB， 负责气体/营养交换的细胞类型）和绒毛外滋养层（EVT，侵袭性细胞类型 在母胎界面）。尽管如此，我们对这些病变的了解仅限于形态学 和一些标记的免疫定位。在过去的几年里，包括我们在内的多个团体， 使用scRNAseq来表征正常和患病胎盘内的细胞异质性; 然而，这些研究仍然主要是描述性的，缺乏分子数据的空间背景， 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，然后进行细胞外基质（ECM）特异性 质谱，作为基于发现的方法，更好地表征特定的MVM和FVM病变 在分子水平上。然后，我们将使用主要术语CTB，以可重复地模拟这些表型， 执行功能验证，作为有针对性的评估方法的一部分。我们将检验这个假设， 妊娠晚期CTB响应于特定细胞和ECM衍生信号而增殖和/或分化成 STB或EVT，从而确定这种独特的瞬时器官的潜在再生能力。 我们还将探索PE相关胎盘功能障碍的细胞和ECM起源，测试PE相关胎盘功能障碍的细胞因子。 假设这种疾病起源于ECM组成和旁分泌信号的改变， 胎盘和蜕膜（母体）细胞。成功完成此提案将建立一个 详细的人类胎盘细胞和基质图谱，具有经验证的结构-功能 关系，为探索胎盘再生能力奠定基础， 胎盘功能障碍