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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709284
• 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.

胚泡植入、胎盘形成和成功的哺乳动物妊娠需要植入部位母胎两侧协调的血管发育/重塑和功能适应。当胚胎附着在母体子宫内层时，丰富的血管子宫内膜对胚胎附着和生长至关重要。植入后不久，这种血管的生长是必要的，以促进营养和氧气运输到发育中的胚胎。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婴串扰调节中起着关键作用。在NSERC-DG项目的支持下，我们已经确定了在猪怀孕早期，子宫内膜淋巴细胞的范式转变功能从细胞毒性到血管生成(促进血管生长)。然而，这些免疫细胞如何被招募到动态的母胎界面或在其妊娠特定功能上的根本问题仍然没有答案。我们假设子宫内膜免疫细胞通过特定的趋化因子信号被招募并定位在猪的母胎界面上。此外，母体免疫细胞和胎儿滋养细胞的功能受microRNAs的调节。利用我们在猪生殖免疫学方面的成熟和有据可查的专业知识，本提案的目标1解决了免疫细胞在怀孕早期是否从子宫内膜前体细胞局部分化或从血液中招募到母胎界面并确定其功能。这项建议的目的2集中在确定miRNA是否调节子宫内膜免疫细胞的发育及其与胎儿滋养层细胞的通讯。在第三个目标中，我们将评估外体在母体免疫细胞和胎儿滋养细胞之间穿梭microRNAs的作用。这些基础性研究将是系统评估驻留在猪子宫内膜的免疫细胞前体及其分化形成新血管发育所需的其他免疫细胞以及胚胎生长过程中其他几个关键过程的第一步。这项研究还将对microRNA介导的母胎细胞之间的交流提供关键的见解。在未来，我们将继续研究动态和不断变化的母胎界面上的免疫调节机制。从该计划中获得的知识将有助于利用生殖过程来提高猪/猪肉行业的胎儿存活率/牛群生产率，也将有助于其他具有类似非侵入性胎盘的家畜，如牛和马。拟议的研究将为2名博士和8名本科生提供培训。