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
• 负责人: Jack D Bui
• 金额: $ 15.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10770207
• 关键词: Administrative Supplement; Alloantigen; Animal Model; Basal Plate; Biological Models; Blood flow; Cell Communication; Cell Differentiation process; Cell Reprogramming; Cells; Data; Decidua; Decidual Cell; Endometrium; Environment; Epithelial Cells; Face; Female; Fetus; First Pregnancy Trimester; Flow Cytometry; Functional disorder; Generations; Goals; Grant; Growth and Development function; Human; Immune; Immune response; Immunofluorescence Immunologic; Inflammatory; Innate Immune Response; Invaded; Knowledge; Leukocytes; Maternal-Fetal Exchange; Mesenchymal Stem Cells; Methods; Modeling; Natural Killer Cells; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Placenta; Placentation; Population; Pregnancy; Pregnant Uterus; Premature Birth; Premature Labor; Process; Publishing; Regenerative Medicine; Reproducibility; Resolution; Resources; Risk; Sendai virus; Series; Sex Differences; Staging; Study models; Surface; Technology; Tissues; Umbilical cord structure; Uterus; Vascular remodeling; Villous; Work; adaptive immune response; amnion; cell bank; cell type; experience; fetal; human model; human pluripotent stem cell; in vitro Model; in vivo; induced pluripotent stem cell; insight; male; maternal immune system; pathogen; programs; response; sex; single-cell RNA sequencing; transcriptomics; trophoblast; vascular abnormality

Project Summary/Abstract The human placenta is a semi-allogeneic tissue whose growth and development requires tolerance by the maternal immune system. In fact, 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. The goal of the original R01 proposal is to evaluate the decidual cell population in both term and preterm birth, then to combine this knowledge with the latest technologies in regenerative medicine to develop in vitro models for the study of dNK-EVT interactions. Specifically, we proposed 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. Given the known association between male fetal sex and risk of preterm birth, we had focused our efforts on characterizing, banking, and reprogramming cells from mom:male baby pairs in the original application. However, to fully understand mechanisms that predispose to sPTB, it would be best to compare these data to those from mom:female baby pairs. Therefore, we now propose to characterize, bank, and reprogram cells from mom:female placenta pairs for this administrative supplement. Successful completion of this proposal will establish a reproducible and manipulatable model system for studying interactions between the maternal immune system and both the male and female placenta.

项目概要/摘要 人胎盘是一种半同种异体组织，其生长发育需要胎盘的耐受性。 母体免疫系统。事实上，母体免疫系统在怀孕期间面临着挑战： 保持对外来胎儿同种异体抗原的耐受性，同时对潜在的反应进行阶段性反应 母胎界面的病原体。胎盘细胞逃避母体的机制 人们对免疫识别知之甚少，特别是在人类怀孕的情况下。子宫 称为蜕膜的内膜是一个特别受研究且重要的微环境，因为它是 称为绒毛外滋养层 (EVT) 的胎盘细胞与母体密切接触的界面 免疫细胞，其中蜕膜自然杀伤（dNK）细胞数量最多。 EVT 具有高度侵入性 适当重塑母体子宫内膜（包括血管）所需的细胞 重塑导致母体血流建立到胎盘。之间的相互作用 已知胎盘 EVT 和蜕膜白细胞通过 EVT 促进母体血管重塑 限制 EVT 侵入子宫壁的程度。事实上，早产问题可能是由于 dNK 细胞的不当反应。不幸的是，dNK 和滋养层之间的相互作用是 由于无法进入蜕膜室，因此很难在持续妊娠中进行研究 发生重要的相互作用。虽然动物模型对这些过程提供了一些见解，但它们 不能准确模拟人类胎盘和妊娠。最初的 R01 提案的目标是 评估足月和早产时的蜕膜细胞群，然后将这些知识与 利用再生医学的最新技术开发用于 dNK-EVT 研究的体外模型 互动。具体来说，我们建议产生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，以便建模 这两种细胞类型之间的相互作用。鉴于男性胎儿性别与风险之间已知的关联 早产时，我们将工作重点放在对来自早产儿的细胞进行表征、储存和重编程上。 妈妈：原申请中的男宝宝成双成对。然而，要充分理解机制 易患 sPTB，最好将这些数据与来自妈妈：女婴的数据进行比较。 因此，我们现在建议对来自妈妈：女性胎盘的细胞进行表征、储存和重新编程 对本行政补充。该提案的成功完成将建立 可重复且可操作的模型系统，用于研究母体免疫之间的相互作用 系统以及男性和女性胎盘。