Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis

多能干细胞：模拟合体滋养层发育和发病机制

基本信息

批准号：
8560788
负责人：
Toshihiko Ezashi
金额：
$ 31.85万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8560788
关键词：
Abbreviations Activins Affect Angiogenic Proteins Anti-Inflammatory Agents Anti-inflammatory Arteries BMP4 Birth Blood Capital Cell Culture Techniques Cell Death Cell fusion Cell model Cells Clinical Complex Conceptus Development Diagnosis Disease Embryo Endocrine Endogenous Retroviruses Endometrial Endothelium Ensure Ethics Event FGF2 gene FLT1 gene Fetal Growth Retardation Fibroblasts First Pregnancy Trimester Gases Genes Gestational Age Goals HERVs Human Human Chorionic Gonadotropin Hypersensitivity Immune In Vitro Inflammatory Inflammatory Response Invaded Lead Letters Longevity Low Birth Weight Infant Mammals Modeling Molecular Mothers Mus Nutrient Oxygen Oxygen measurement, partial pressure, arterial Pathogenesis Pathology Pattern Perfusion Phenotype Placenta Placenta Diseases Placentation Pluripotent Stem Cells Pre-Eclampsia Pregnancy Pregnancy Outcome Pregnancy loss Premature Birth Process Production Progesterone Property Proteins Role Signal Transduction Small Inducible Cytokine A3 Source Spiral Artery of the Endometrium Staging Stem cells Structure Study models Syncytiotrophoblast System Taxon Testing Time Tissues Umbilical cord structure Villous Waste Products activin A base cell type cytokine cytotrophoblast early onset embryonic stem cell human embryonic stem cell in vitro Model in vivo induced pluripotent stem cell inhibitor/antagonist insight novel diagnostics offspring public health relevance release factor surface coating syncytin transcription factor treatment strategy trophoblast

项目摘要

DESCRIPTION (provided by applicant): A placenta allows eutherian mammals to give birth to progeny that are already developmentally advanced. A wide range of placental phenotypes exist across taxa to ensure adequate nutrient transfer from mother to offspring. The human placenta forms particularly intimate associations with maternal tissues through two types of cells: 1) syncytiotrophoblast (STB) cells, the fetally-derived trophoblast (TB) cell subset that coats the surface of the villous placenta, and 2) extravillous TB (EVCTB), which invade deeply, interact with maternal decidual immune cells, and remodel the spiral arteries. Both TB subsets are in direct contact with maternal blood and maternal immune cells and both are derived from an ill-defined, stem-cell like, cytotrophoblast (cytoTB) cell subpopulation. Although many adverse pregnancy outcomes may result from poor placental development, the study of the earliest stages of placental development cannot be performed in humans for ethical reasons. For example, alterations in STB development and turnover have been implicated in placental disease, including preeclampsia (PE), the leading single cause of premature birth. STB is the source of "placental debris", cytokines, and pro-inflammatory and anti-angiogenic proteins, which become elevated in mothers diagnosed with PE. Appropriate in vitro models of early placental development are essential if we are to better understand and treat diseases of poor placentation. The first goal of this proposal is to generate STB and its mononucleated precursors from human embryonic stem cells (hESC) that have been treated with BMP4 (BMP-hESC) and inhibitors of activin and FGF2 signaling. We will use this system as a model to study STB emergence, especially the process of cell fusion and cell death, as well as intrinsic and extrinsic factors that influence these transitions. This project has high significance because STB forms the major interface with maternal blood perfusing the placenta and is responsible for the production of endocrine factors such as hCG and exchange of gases, nutrients and waste products The second goal is to demonstrate the utility of the BMP-hESC model to examine the molecular events controlling STB formation and lifespan, with an emphasis on the roles of transcription factors, such as GCM1 & GATA2, fusogenic proteins such syncytin-1 & -2 (ERVW1, ERVFRD-1, respectively) and a presently little understood HERV envelope gene product (ERV-Fb1) that inhibits cell-cell fusion. A third goal is to assess whether some features of PE can be unearthed in the BMP-hESC model. Our hypothesis is that TB from a sub-group of conceptuses whose mothers develop PE early in their pregnancies is unusually sensitive to high oxygen tensions. Since STB will only begin to encounter well-oxygenated maternal blood after the uteroplacental arteries "open" towards the end of the first trimester of pregnancy, the oxygen hypersensitivity of cells derived from PE placentas may cause them to turnover at an accelerated rate and shed cell contents and debris into the circulating maternal blood more quickly than normal STB. We will test this hypothesis in vitro using iPSCs derived from the umbilical cords of babies born to mothers with severe preeclampsia and gestational age-matched control iPSCs.

描述（由申请人提供）：胎盘可以让真兽类哺乳动物产下已经发育成熟的后代。跨类群存在多种胎盘表型，以确保从母亲到后代的充足营养转移。人类胎盘通过两种类型的细胞与母体组织形成特别密切的联系：1）合体滋养层（STB）细胞，即覆盖绒毛胎盘表面的胎儿来源的滋养层（TB）细胞亚群，2）绒毛外结核（EVCTB）），深入侵入，与母体蜕膜免疫细胞相互作用，重塑螺旋动脉。两种结核亚群均与母体血液和母体免疫细胞直接接触，并且均源自不明确的干细胞样细胞滋养层 (cytoTB) 细胞亚群。尽管许多不良妊娠结局可能是由于胎盘发育不良造成的，但出于伦理原因，胎盘发育最早阶段的研究无法在人类身上进行。例如，STB 发育和更新的改变与胎盘疾病有关，包括先兆子痫 (PE)，这是早产的主要单一原因。 STB 是“胎盘碎片”、细胞因子以及促炎和抗血管生成蛋白的来源，这些蛋白在诊断为 PE 的母亲中会升高。如果我们要更好地了解和治疗胎盘发育不良疾病，适当的早期胎盘发育体外模型至关重要。该提案的第一个目标是从经过 BMP4 (BMP-hESC) 以及激活素和 FGF2 信号传导抑制剂处理的人胚胎干细胞 (hESC) 中产生 STB 及其单核前体。我们将使用该系统作为模型来研究STB的出现，特别是细胞融合和细胞死亡的过程，以及影响这些转变的内在和外在因素。该项目具有很高的意义，因为 STB 形成了与灌注胎盘的母体血液的主要界面，并负责 hCG 等内分泌因子的产生以及气体、营养物质和废物的交换。第二个目标是展示 BMP 的实用性hESC 模型用于检查控制 STB 形成和寿命的分子事件，重点是转录因子（如 GCM1 和 GATA2）、融合蛋白（如合胞素 1 和 -2）（ERVW1、 ERVFRD-1）和目前知之甚少的HERV包膜基因产物（ERV-Fb1），其抑制细胞与细胞的融合。第三个目标是评估是否可以在 BMP-hESC 模型中发现 PE 的某些特征。我们的假设是，来自一组受孕者的结核病对高氧张力异常敏感，这些受孕者的母亲在怀孕早期患上肺栓塞。由于 STB 仅在妊娠前三个月末子宫胎盘动脉“打开”后才开始接触氧合良好的母体血液，因此来自 PE 胎盘的细胞对氧的超敏性可能会导致它们加速更新并脱落细胞内容物和碎片比正常 STB 更快地进入循环母体血液。我们将使用来自患有严重先兆子痫的母亲所生婴儿的脐带的 iPSC 和孕龄匹配的对照 iPSC 在体外测试这一假设。