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: 9084586
• 负责人: Toshihiko Ezashi
• 金额: $ 31.53万
• 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/9084586
• 关键词: Activins; Affect; Angiogenic Proteins; Anti-Inflammatory Agents; Anti-inflammatory; Arteries; BMP4; Birth; Blood; Cell Culture Techniques; Cell Death; Cell fusion; Cell model; Cells; Clinical; Complex; Conceptus; Development; Diagnosis; Disease; Endocrine; Endogenous Retroviruses; Endometrial; Endothelium; Ensure; Ethics; Event; FGF2 gene; FLT1 gene; Fetal Growth Retardation; First Pregnancy Trimester; GCM1 gene; Gases; Gestational Age; Goals; Health; Human; Human Chorionic Gonadotropin; Hypersensitivity; Immune; In Vitro; Inflammatory; Inflammatory Response; Invaded; Lead; Longevity; Low Birth Weight Infant; Mammals; Modeling; Molecular; Mothers; Nutrient; Oxygen; Pathogenesis; Pathology; Pattern; Perfusion; Phenotype; Placenta; Placenta Diseases; Placentation; Pluripotent Stem Cells; Pre-Eclampsia; Pregnancy; 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; adverse pregnancy outcome; base; cell type; cytokine; cytotrophoblast; early onset; gene product; human embryonic stem cell; in vitro Model; in vivo; induced pluripotent stem cell; insight; novel diagnostics; offspring; 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Eutherian哺乳动物生下已经发育进发的后代。整个分类单元中都存在各种胎盘表型，以确保从母亲到后代的足够营养转移。人胎盘通过两种细胞特别与母体组织形成密切的关联：1）合成肌植物细胞（STB）细胞，胎儿衍生的滋养细胞（TB）细胞子集，绒毛的表面覆盖了绒毛的表面，以及2）散发性TB（EVCTB），这些细胞与造成的细胞相互作用，并与造成的细胞相互作用，并与造成的杂物相互作用，并散布了杂物。这两个结核病子集都与母体血液和母体免疫细胞直接接触，并且均来自不确定的干细胞，例如细胞增多质细胞（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而导致的，但由于道德原因，无法在人类中对胎盘发育的最早阶段进行研究。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），这是早产的主要原因。 STB是“胎盘碎屑”，细胞因子以及促炎和抗血管生成蛋白的来源，在被诊断为PE的母亲中，它们升高。如果我们要更好地理解和治疗胎盘不良的疾病，那么适当的早期胎盘发育模型至关重要。该提案的第一个目标是从已通过BMP4（BMP-HESC）处理的人类胚胎干细胞（HESC）产生STB及其单核前体，以及激活素和FGF2信号传导的抑制剂。我们将使用该系统作为研究STB出现的模型，尤其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。 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蛋白这样的Syncytin-1＆-2（分别为ERVW1，ERVFRD-1）和目前几乎没有理解的HERV包膜基因产物（ERV-FB1）抑制细胞细胞融合。第三个目标是评估BMP-HESC模型中是否可以发掘PE的某些特征。我们的假设是，来自母亲在怀孕早期出现PE的概念子组的结核病异常敏感。由于在妊娠头三个月结束时，STB仅在子宫酸性动脉“开放”之后才开始遇到氧化良好的孕产妇血液，因此从PE胎盘胎盘衍生出的细胞的氧超敏性可能会导致它们以加速的速度和脱落的细胞内容物和脱离循环的产生血液的流失，并降低造成的含量。我们将在体外使用IPSC在体外测试这一假设，这些IPSC源自具有严重的先兆子痫和胎龄匹配的对照IPSC的母亲出生的婴儿的脐带。