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: 10549321
• 负责人: Jack D Bui
• 金额: $ 49.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10549321
• 关键词: Alloantigen; Animal Model; Apoptosis; Biological Assay; Biological Models; Blood; Blood flow; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Coculture Techniques; Data; Decidua; Decidual Cell; Endometrium; Environment; Epithelial Cells; Face; Fetus; First Pregnancy Trimester; Flow Cytometry; Functional disorder; Galactose Binding Lectin; Gene Expression; Generations; Goals; Growth and Development function; Human; Hypoxia; Immune; Immune Evasion; Immune response; Immunofluorescence Immunologic; Inflammatory; Innate Immune Response; Interleukin-15; Invaded; Knowledge; Leukocytes; Maternal-Fetal Exchange; Mesenchymal Stem Cells; Methods; Modeling; Natural Killer Cells; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Placenta; Placentation; Pluripotent Stem Cells; Population; Pregnancy; Pregnant Uterus; Premature Birth; Premature Labor; Process; Protocols documentation; Publishing; Regenerative Medicine; Reproducibility; Research Personnel; Resolution; Resources; Risk; Sendai virus; Series; Staging; Stromal Cell-Derived Factor 1; Study models; Surface; Technology; Tissues; Umbilical cord structure; Uterus; Vascular remodeling; Villous; Work; adaptive immune response; amnion; cell type; cytokine; cytotoxic; cytotoxicity; experience; fetal; human model; human pluripotent stem cell; in vitro Model; in vivo; induced pluripotent stem cell; insight; male; maternal immune system; pathogen; peripheral blood; programs; response; single-cell RNA sequencing; transcriptomics; trophoblast; vascular abnormality

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.

人胎盘是一种半合成组织，其生长和发育需要母体免疫系统的耐受性。胎盘细胞与孕产妇血液和子宫组织密切接触，但在正常怀孕过程中能够逃避免疫识别。孕产妇免疫系统在怀孕期间面临挑战：保持对外国胎儿同抗原的耐受性，同时对母亲 - 狂热界面的潜在病原体产生反应。胎盘细胞逃避母体免疫识别的机制知之甚少，尤其是在人类怀孕的情况下。子宫衬里称为Decidua，是一种特别研究且重要的微环境，因为它是胎盘细胞称为胎盘跨滋养细胞（EVT）与母体免疫细胞密切接触的胎盘细胞，其中dect骨自然杀伤力（DNK）细胞是最丰富的。 EVT是高度侵入性的细胞，需要正确重塑母体子宫内膜，包括血管重塑，从而导致产妇血液流向胎盘。已知胎盘EVT和decial骨白细胞之间的相互作用可通过EVT促进母体血管重塑，并限制EVT侵袭对子宫壁的程度。实际上，早产的问题可能是由于DNK细胞的不适当反应引起的。不幸的是，由于缺乏进入这些重要相互作用的判决室的机会，DNK与滋养细胞之间的相互作用很难在持续的怀孕中进行研究。尽管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对人类胎盘和怀孕进行建模。该提案旨在以系统的，详细的方式评估学期和早产的决策细胞种群，然后将这些知识与再生医学中最新技术相结合，以开发体外模型，以研究DNK-EVT相互作用。在过去的几年中，我们的研究人员合作团队建立了优化的方法，以将多能干细胞分化为NK细胞和EVT。现在，我们建议生成匹配的母体和胎盘诱导的多能干细胞（IPSC），并分别将这些细胞区分为DNK细胞和EVT，以模拟这两种细胞类型之间的相互作用。该提案的成功完成将建立一个可再现且可操作的模型系统，用于研究胎盘和母体免疫系统之间的相互作用，并有可能导致鉴定机制，这些机制通过这些机制增加了这些相互作用的异常，这会增加特发性自发早产的风险。