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

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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. **