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Modeling Human Placentation via Single Cell RNA-Sequencing

通过单细胞 RNA 测序模拟人类胎盘

基本信息

批准号：
10316877
负责人：
Soumen Paul
金额：
$ 23.1万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2021-07-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316877
关键词：
Adult Affect Bioinformatics Biology Birth Blood Vessels Caring Cell Differentiation process Cell Lineage Cell Nucleus Cells Chorionic Villi Sampling Chorionic villi Clinical Data Data Defect Development Diagnostic Disease Embryo Ensure Ethics Family Fetal Growth Retardation Fetal health First Pregnancy Trimester Functional disorder GATA3 gene Gases Gene Expression Profile Gene Expression Profiling Genomics Gestational Age Gestational Diabetes Healthcare Hormones Human Impairment Institutes Kansas Laboratories Lead Maintenance Maternal Mortality Mediating Medical center Modeling Modernization Molecular Monitor Mothers Nutrient Pathologic Pathway interactions Patients Placenta Placenta Diseases Placentation Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Pregnancy loss Premature Birth Procedures Process Proliferating Public Health Publishing Research Resolution Risk Sampling Small Nuclear RNA Source Spontaneous abortion Syncytiotrophoblast System Technology Testing Time Tissues Undifferentiated Universities Villous cell type combinatorial comparative cytotrophoblast delivery complications early pregnancy loss experimental analysis experimental study fetal follow-up human model innovation insight knockout gene longitudinal analysis mouse genetics mouse model mutant mouse model natural Blastocyst Implantation postnatal pregnancy disorder progenitor self-renewal single-cell RNA sequencing success transcription factor transcriptome sequencing trophoblast trophoblast stem cell

项目摘要

Abstract Placental dysfunction leads to pregnancy-associated disorders, including intrauterine growth restriction (IUGR) and preeclampsia, and also serves as a developmental cause for postnatal and adult diseases. Often, the causal alterations in the placentation process, which lead to defective pregnancies, occur early in gestation. However, due to ethical barriers and difficulties with the experimental systems, most of the studies on human placental function are performed with samples obtained at term, thereby, limiting our ability to understand placental development and function throughout gestation. Fortunately, the recent advancement of single-nucleus RNA-sequencing (snRNA-seq) strategy and success in deriving true human trophoblast stem cells (human TSCs) from villous cytotrophoblast cells (CTBs) have opened up new strategies for direct assessment of early human placentation process. Chorionic villus sampling (CVS) is a standard health care procedure performed during latter stages of the first trimester of pregnancy. Surplus tissue obtained via CVS represents a valuable source of trophoblast cells for experimental analysis and thus, a unique opportunity to interrogate the early developing placenta. Using gene knockout mouse models, we discovered that depletion of GATA family of transcription factors, GATA2 and GATA3 in trophoblast progenitor cells leads to either loss of pregnancy or fetal growth restriction. As part of our pursuit to define importance of these findings with respect to human placentation, we have successfully performed scRNA-seq study with human chorionic villous samples and found that, within a first-trimester placenta, GATA2 and GATA3 are broadly expressed in distinct cell types, including CTBs, syncytioytrophoblasts (SynTs) and extravillous trophoblasts (EVTs). Furthermore, we have also been able to establish human TSCs from CTBs, isolated from chorionic villi, and found that loss of GATA2 expression in human TSCs impairs both EVT and SynTB differentiation. These observations led us to the central hypothesis of this proposal that single cell gene expression patterns, including expression of GATA factors, in a first-trimester placenta could be predictive of pregnancy associated disorders during late gestation. To test this hypothesis, we will use CVS to perform snRNA-seq and to establish patient-specific human TSCs for subsequent functional studies. We will also monitor those pregnancies for pregnancy- associated disorders, including intrauterine growth restriction and preeclampsia and collect term placental samples for follow up analyses. Together, our proposed study, bolstered by modern technologies, will illuminate previously unknown pathways, which underlie placental adaptation at a single cell level during normative and pathological pregnancies.

摘要