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

• 批准号: 8720806
• 负责人: Toshihiko Ezashi
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 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/8720806
• 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

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）：胎盘允许真兽目哺乳动物生育已经发育成熟的后代。不同分类群间存在着广泛的胎盘表型，以确保从母体到后代有足够的营养转移。人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，和2）绒毛外TB（EVCTB），其深入侵入，与母体蜕膜免疫细胞相互作用，并重塑螺旋动脉。两种TB亚群都与母体血液和母体免疫细胞直接接触，并且都来源于不明确的干细胞样细胞滋养层（cytoTB）细胞亚群。虽然许多不良妊娠结局可能是由胎盘发育不良引起的，但出于伦理原因，不能在人类中进行胎盘发育最早阶段的研究。例如，STB发育和周转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的母亲中升高。如果我们要更好地了解和治疗胎盘不良疾病，早期胎盘发育的适当体外模型是必不可少的。该提议的第一个目标是从已经用BMP 4（BMP-hESC）和激活素和FGF 2信号传导的抑制剂处理的人胚胎干细胞（hESC）产生STB及其单核前体。我们将使用这个系统作为一个模型来研究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形成与母体血液灌注胎盘的主要界面，并负责内分泌因子如hCG的产生以及气体、营养物和废物的交换。第二个目标是证明BMP-hESC模型用于检查控制STB形成和寿命的分子事件的实用性，重点是转录因子的作用，如GCM 1和GATA 2，融合蛋白如合胞素-1和-2（分别为ERVW 1、ERVFRD-1）和目前很少了解的抑制细胞-细胞融合的HERV包膜基因产物（ERV-Fb 1）。第三个目标是评估PE的一些特征是否可以在BMP-hESC模型中发掘出来。我们的假设是，结核病从一个小组的概念，其母亲在怀孕早期发展PE是异常敏感的高氧张力。由于STB将仅在子宫胎盘动脉“打开”之后开始遇到充分含氧的母体血液，接近妊娠的前三个月结束，因此来自PE胎盘的细胞的氧超敏性可能导致它们以加速的速率周转，并且比正常STB更快地将细胞内容物和碎片脱落到循环母体血液中。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和胎龄匹配的对照iPSC在体外测试这一假设。