Hematopoietic and Immune Development in the Human Chorion

人类绒毛膜的造血和免疫发育

• 批准号: 10608180
• 负责人: MARCUS O MUENCH
• 金额: $ 66.24万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-11 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608180
• 关键词: Active Sites; Activities of Daily Living; Address; Anti-Inflammatory Agents; Biological Assay; Biology; Blood Cells; CD34 gene; California; Cell Culture Techniques; Cell Line; Cell Separation; Cells; Cerebral Palsy; Chorion; Chronic; Collaborations; Data; Decidua; Development; Embryo; Endometrium; Fetal Membranes; Fetus; First Pregnancy Trimester; Flow Cytometry; Fostering; Gene Expression; Gestational Age; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Human Development; Immune; Immune system; Immunity; Immunodeficient Mouse; Immunologics; In Situ; In Vitro; Infection; Infection prevention; Invaded; Laboratories; Low Birth Weight Infant; Lymphocyte; Macrophage; Maternal-Fetal Exchange; Modeling; Mothers; Myelogenous; Myelopoiesis; Pathologic; Phenotype; Placenta; Play; Population; Pregnancy; Premature Birth; Production; Proliferating; Regulation; Reporting; Research Institute; Role; San Francisco; Sentinel; Site; Spleen; Supporting Cell; Surface; T cell regulation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Transplantation; Universities; Villus; Work; amnion; cell type; cytokine; cytotrophoblast; embryo tissue; embryo/fetus; experimental study; fetal; first responder; hematopoietic tissue; immunoregulation; in vitro Assay; inflammatory milieu; insight; intraamniotic infection; maternal immune system; mesenchymal stromal cell; microorganism; monocyte; neonatal death; prenatal; prevent; progenitor; protein expression; source localization; stem cell population; transplant model; trophoblast stem cell; ward

Project Summary/Abstract: Hematopoiesis occurs at multiple sites during human prenatal development. In addition to the primary intraembryonic hematopoietic tissues, it is now recognized that the extra-embryonic tissues – the placenta and chorion – contain hematopoietic stem cells. The presence of hematopoietic stem cells in these tissues raises the possibility that they actively contribute to the pool of blood cells contained in the extra-embryonic tissues. In this proposal we focus on the human fetal membranes, specifically the chorion. Macrophages are present in the chorion and presumably act as sentinels and first responders to infection as well as invasion by maternal cells. The presence of these macrophages suggests that the chorion is not just an inert physical barrier. We hypothesize that the human chorion is an immunologically active barrier containing macrophages that develop in situ from hematopoietic stem cells that together with other cells in the chorion maintain the maternal-fetal interface to prevent infection and immune rejection of the fetus during pregnancy. In the first of three specific aims, we will investigate if chorionic hematopoietic stem cells serve as a local source of precursors for monocytic cells found in the chorion. Tissues across a range of gestational ages will be examined using flow cytometry, hematopoietic progenitor cultures, and a transplant model, using immunodeficient mice, to determine the types of hematopoietic precursors that exist in the chorion. Experiments will focus on demonstrating active myelopoiesis in the chorion. In the second aim, we will explore the role of the chorionic microenvironment in the development and function of macrophages. Mesenchymal stromal cells and cytotrophoblasts comprise the hematopoietic niche in the chorion, which will be studied in culture to test their effects on monocyte development and macrophage maturation. We hypothesize that these cell types support the development of M2 macrophages to foster an anti-inflammatory environment in the chorion. This will be more specifically tested in the third aim, in which we will investigate the immunomodulatory role of chorion cells in preventing rejection by maternal T-cells. Preliminary data show the presence of T cells in the chorion of both maternal and fetal origin. The origins and distribution of T-cells in the chorion will be further investigated at different gestations. Additionally, we will determine if the T-cells are active and if they are enriched in any specific T-cell subtypes. T-cells from the adjacent decidua will be analyzed for comparison as well as fetal T-cells from the spleen. We will explore the roles of chorionic macrophages, mesenchymal stromal cells, and cytotrophoblasts in the regulation of T-cell activation. Together these aims will show that chorionic macrophages develop locally from a population of stem cells in the chorion. Also, that these macrophages, in conjunction to other cell cellular populations contribute to generate an active immunological barrier at the extensive maternal-fetal interface that includes the fetal membranes, which function to ward off infection and invasion of maternal lymphocytes.

项目摘要/摘要：造血作用发生在人类产前发育过程中的多个部位。 除了初级胚胎内造血组织外，现在人们认识到，胚胎外造血组织 组织——胎盘和绒毛膜——含有造血干细胞。 这些组织中的细胞提出了一种可能性，即它们积极地为血液中所含的血细胞库作出贡献。 在本提案中，我们重点关注人类胎膜，特别是绒毛膜。 巨噬细胞存在于绒毛膜中，可能充当感染的哨兵和第一反应者 这些巨噬细胞的存在表明绒毛膜不仅仅是一个细胞。 我们勇敢地承认，人类绒毛膜是一个免疫活性屏障，其中含有 由造血干细胞与绒毛膜中的其他细胞一起原位发育的巨噬细胞 维持母胎界面，防止妊娠期间胎儿感染和免疫排斥反应。 在三个具体目标中的第一个中，我们将研究绒毛膜造血干细胞是否可以作为局部造血干细胞。 在不同孕龄的绒毛膜组织中发现的单核细胞的前体来源。 使用流式细胞术、造血祖细胞培养物和移植模型进行检查，使用 免疫缺陷小鼠，以确定绒毛膜中存在的造血前体细胞的类型。 实验的重点是展示绒毛膜中活跃的骨髓生成。在第二个目标中，我们将探索。 绒毛膜微环境在巨噬细胞发育和功能中的作用。 基质细胞和细胞滋养层构成了绒毛膜中的造血生态位，这将在以下研究中进行研究 培养以测试它们对单核细胞发育和巨噬细胞成熟的影响。 细胞类型支持 M2 巨噬细胞的发育，以在体内营造抗炎环境 这将在第三个目标中进行更具体的测试，我们将在其中调查绒毛膜。 绒毛膜细胞在预防母体 T 细胞排斥反应中的免疫调节作用。 母体和胎儿绒毛膜中存在 T 细胞 T 细胞在母体和胎儿中的起源和分布。 此外，我们将在不同妊娠期进一步研究绒毛膜，以确定 T 细胞是否存在。 活跃，并且如果它们富含来自邻近蜕膜的任何特定 T 细胞亚型。 进行比较以及来自脾脏的胎儿 T 细胞我们将探讨绒毛膜的作用。 巨噬细胞、间充质基质细胞和细胞滋养层共同调节 T 细胞活化。 这些目标将表明绒毛膜巨噬细胞是由绒毛膜中的干细胞群局部发育的。 此外，这些巨噬细胞与其他细胞群一起有助于产生活性 包括胎膜在内的广泛母胎界面上的免疫屏障， 具有抵御母体淋巴细胞感染和侵袭的作用。