Modeling human trophoblast-NK cell interactions in term and preterm birth
足月和早产时人类滋养层 - NK 细胞相互作用的建模
基本信息
- 批准号:10549321
- 负责人:
- 金额:$ 49.31万
- 依托单位:
- 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:2021-04-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AlloantigenAnimal ModelApoptosisBiological AssayBiological ModelsBloodBlood flowCell CommunicationCell Differentiation processCell physiologyCellsCoculture TechniquesDataDeciduaDecidual CellEndometriumEnvironmentEpithelial CellsFaceFetusFirst Pregnancy TrimesterFlow CytometryFunctional disorderGalactose Binding LectinGene ExpressionGenerationsGoalsGrowth and Development functionHumanHypoxiaImmuneImmune EvasionImmune responseImmunofluorescence ImmunologicInflammatoryInnate Immune ResponseInterleukin-15InvadedKnowledgeLeukocytesMaternal-Fetal ExchangeMesenchymal Stem CellsMethodsModelingNatural Killer CellsPatientsPeripheral Blood Mononuclear CellPhenotypePlacentaPlacentationPluripotent Stem CellsPopulationPregnancyPregnant UterusPremature BirthPremature LaborProcessProtocols documentationPublishingRegenerative MedicineReproducibilityResearch PersonnelResolutionResourcesRiskSendai virusSeriesStagingStromal Cell-Derived Factor 1Study modelsSurfaceTechnologyTissuesUmbilical cord structureUterusVascular remodelingVillousWorkadaptive immune responseamnioncell typecytokinecytotoxiccytotoxicityexperiencefetalhuman modelhuman pluripotent stem cellin vitro Modelin vivoinduced pluripotent stem cellinsightmalematernal immune systempathogenperipheral bloodprogramsresponsesingle-cell RNA sequencingtranscriptomicstrophoblastvascular abnormality
项目摘要
The human placenta is a semi-allogeneic tissue whose growth and development requires tolerance by the maternal immune system. Placental cells come in close contact with maternal blood and uterine tissues yet are able to evade immune recognition during the course of a normal pregnancy. The maternal immune system faces a challenge during pregnancy: to maintain tolerance toward foreign fetal alloantigens while simultaneously staging a response to potential pathogens at the maternal-fetal interface. The mechanisms through which placental cells evade maternal immune recognition are poorly understood, particularly in the context of human pregnancy. The uterine lining, called decidua, is a particularly understudied and important microenvironment, because it is the interface where placental cells called extravillous trophoblast (EVT) come in close contact with maternal immune cells, of which decidual natural killer (dNK) cells are the most abundant. EVT are highly invasive cells which are required for proper remodeling of the maternal uterine lining, including vascular remodeling which leads to establishment of maternal blood flow to the placenta. Interactions between placental EVT and decidual leukocytes are known to facilitate maternal vascular remodeling by EVT and limit the extent of EVT invasion into the uterine wall. Indeed, problems in preterm birth could result from inappropriate responses by dNK cells. Unfortunately, interactions between dNK and trophoblasts are difficult to study in an ongoing pregnancy, due to lack of access to the decidual compartment, where these important interactions occur. While animal models have offered some insights into these processes, they do not accurately model human placentation and pregnancy. This proposal aims to evaluate the decidual cell population in both term and preterm birth in a systematic, detailed manner, then to combine this knowledge with the latest technologies in regenerative medicine in order to develop in vitro models for the study of dNK-EVT interactions. Over the past few years, our collaborative team of investigators has established optimized methods for differentiation of pluripotent stem cells into both NK cells and EVT. We now propose to generate matched maternal and placental induced pluripotent stem cells (iPSC), and differentiate these cells into dNK cells and EVT, respectively, in order to model interactions between these two cell types. Successful completion of this proposal will establish a reproducible and manipulatable model system for studying interactions between the placenta and maternal immune system and has the potential to lead to identification of mechanisms through which abnormalities in these interactions increase the risk of idiopathic spontaneous preterm birth.
人类胎盘是一种半异体组织,其生长和发育需要母体免疫系统的耐受。胎盘细胞与母体血液和子宫组织密切接触,但在正常妊娠期间能够逃避免疫识别。在怀孕期间,母体免疫系统面临着一个挑战:维持对外来胎儿异体抗原的耐受性,同时在母胎界面对潜在的病原体进行反应。胎盘细胞逃避母体免疫识别的机制尚不清楚,特别是在人类怀孕的情况下。子宫内膜(称为蜕膜)是一个特别未被充分研究的重要微环境,因为它是胎盘细胞(称为上皮外滋养细胞(EVT))与母体免疫细胞密切接触的界面,其中蜕膜自然杀伤细胞(dNK)最丰富。EVT是高度侵袭性细胞,是母体子宫内膜重建所必需的,包括血管重建,从而建立母体血液流向胎盘。已知胎盘EVT和蜕膜白细胞之间的相互作用可促进EVT对母体血管的重塑,并限制EVT侵入子宫壁的程度。事实上,早产的问题可能是由dNK细胞的不适当反应引起的。不幸的是,由于无法进入发生这些重要相互作用的蜕膜室,因此在妊娠期间很难研究dNK和滋养细胞之间的相互作用。虽然动物模型对这些过程提供了一些见解,但它们并不能准确地模拟人类的胎盘和怀孕。本研究旨在系统、详细地评估足月和早产儿的蜕膜细胞群,然后将这些知识与再生医学的最新技术相结合,以建立体外模型来研究dNK-EVT相互作用。在过去的几年中,我们的合作研究团队已经建立了多能干细胞分化为NK细胞和EVT的优化方法。我们现在建议生成匹配的母体和胎盘诱导多能干细胞(iPSC),并将这些细胞分别分化为dNK细胞和EVT,以模拟这两种细胞类型之间的相互作用。该建议的成功完成将为研究胎盘和母体免疫系统之间的相互作用建立一个可重复和可操作的模型系统,并有可能导致识别这些相互作用异常增加特发性自发性早产风险的机制。
项目成果
期刊论文数量(0)
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{{ truncateString('Jack D Bui', 18)}}的其他基金
Modeling human trophoblast-NK cell interactions in term and preterm birth
足月和早产时人类滋养层 - NK 细胞相互作用的建模
- 批准号:
10770207 - 财政年份:2023
- 资助金额:
$ 49.31万 - 项目类别:
Modeling human trophoblast-NK cell interactions in term and preterm birth
足月和早产时人类滋养层 - NK 细胞相互作用的建模
- 批准号:
10211100 - 财政年份:2021
- 资助金额:
$ 49.31万 - 项目类别:
Modeling human trophoblast-NK cell interactions in term and preterm birth
足月和早产时人类滋养层 - NK 细胞相互作用的建模
- 批准号:
10370386 - 财政年份:2021
- 资助金额:
$ 49.31万 - 项目类别:
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