Regulation of immune cell recruitment and angiogenesis at the maternal-fetal interface in pigs

猪母胎界面免疫细胞募集和血管生成的调节

• 批准号: RGPIN-2016-04816
• 负责人: Tayade, Chandrakant
• 金额: $ 2.77万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746100
• 关键词: Regulation; immune; cell; recruitment; angiogenesis

Blastocyst implantation, placentation and successful mammalian pregnancy require coordinated blood vessel development/ remodeling and functional adaptations on both maternal-fetal sides of implantation sites. At the time of embryo attachment to the maternal uterine lining, a richly vascularized endometrium is critical for successful embryo attachment and growth. Shortly after implantation, growth of this vasculature is essential to facilitate nutrients and oxygen transport to the developing conceptus. Immune cells, in particular natural killer cells, T cells, dendritic cells and macrophages are recruited to the implantation sites in pigs where they have pivotal roles in blood vasculature development and regulation of maternal-fetal cross talk. With support from NSERC-DG program, we have identified paradigm shift functions of endometrial lymphocytes from being cytotoxic to angiogenic (blood vessel growth promoting) during early pig pregnancy. However, fundamental question of how these immune cells recruited to the dynamic maternal-fetal interface or on their pregnancy specific functions are remain unanswered. We hypothesize that endometrial immune cells are recruited and positioned within the porcine maternal-fetal interface by specific chemokine signals. Further, the functions of maternal immune cells and fetal trophoblasts are regulated by microRNAs. Using our established and documented expertise in porcine reproductive immunology, Aim 1 of this proposal addresses whether immune cells differentiate locally from endometrial progenitors or recruited from blood to the maternal-fetal interface during early pregnancy and identify their functions. Aim 2 of this proposal is focused on determining whether miRNA regulate endometrial immune cell development and their communication with fetal trophoblasts. In the third Aim, we will evaluate role of exosomes in shuttling microRNAs between maternal immune cells and fetal trophoblasts. These foundational studies will be the first step in systematic evaluation of immune cell progenitors residing in the pig endometrium and their differentiation to form other immune cells required for new blood vessel development and several other key processes during the conceptus growth. This research will also provide key insights into microRNA mediated communication between maternal and fetal cells. In the future, we will continue investigation around immunoregulatory mechanisms at the dynamic and ever changing maternal-fetal interface. Knowledge gained from this program will help exploit reproductive processes for improvement in fetal survival/herd productivity not only for pig/pork industry but also for other domestic animals with similar non-invasive placentation such as cattle and horse. Proposed research will provide training for 2 PhD and 8 undergraduate students.

胚泡着床、胎盘和哺乳动物成功怀孕需要着床部位母胎双方血管发育/重塑和功能适应的协调。在胚胎附着于母体子宫内膜时，血管丰富的子宫内膜是胚胎成功附着和生长的关键。植入后不久，这一血管系统的生长对于促进营养和氧气运输到发育中的胎儿是必不可少的。免疫细胞，特别是自然杀伤细胞、T细胞、树突状细胞和巨噬细胞被招募到猪的植入部位，在那里它们在血管发育和母胎串扰的调节中起着关键作用。在NSERC-DG项目的支持下，我们已经确定了子宫内膜淋巴细胞在猪妊娠早期从细胞毒性到血管生成（促进血管生长）的模式转变功能。然而，这些免疫细胞如何招募到动态母胎界面或其妊娠特异性功能的基本问题仍未得到解答。我们假设子宫内膜免疫细胞通过特定的趋化因子信号被募集并定位在猪母胎界面。此外，母体免疫细胞和胎儿滋养细胞的功能受microrna调控。利用我们在猪生殖免疫学方面已建立和记录的专业知识，本提案的目的1解决了免疫细胞是否从子宫内膜祖细胞局部分化或在妊娠早期从血液募集到母胎界面并确定其功能。本提案的目的2集中于确定miRNA是否调节子宫内膜免疫细胞的发育及其与胎儿滋养细胞的通讯。在第三个目标中，我们将评估外泌体在母体免疫细胞和胎儿滋养细胞之间穿梭microrna的作用。这些基础研究将是系统评估猪子宫内膜中免疫细胞祖细胞及其分化形成新血管发育和怀孕期间其他关键过程所需的其他免疫细胞的第一步。这项研究也将为母胎细胞之间的microRNA介导的通讯提供关键的见解。在未来，我们将继续围绕动态和不断变化的母胎界面的免疫调节机制进行研究。从该项目中获得的知识将有助于利用生殖过程来提高胎儿存活率/群体生产力，不仅适用于猪/猪肉行业，也适用于其他具有类似非侵入性胎盘的家畜，如牛和马。拟进行的研究将培养2名博士和8名本科生。