The placenta plays an essential role in supporting the growth and development of the fetus. Specialised trophoblast cells cover the surface of this organ, a subset of which also invade into the maternal endometrium remodelling the uterine spiral arteries to provide efficient blood flow to the developing feto-placental unit. Interaction of maternal immune cells with the trophoblast aids both placental development and function, and maternal immunotolerance to the semi-allogenic feto-placental unit. This includes circulating immune cells, immune cells resident in the decidua and placental macrophages. Dysfunction in immune cell-trophoblast interactions is associated with complications of pregnancy including preeclampsia, fetal growth restriction and preterm birth. However, we still have very little knowledge about the exact mechanism behind these interactions, in both health and disease. A new research field has opened up in recent years, focused on the role of exosomes (a type of extracellular vesicle) in cell-cell communication. Exosomes can be taken up by recipient cells, resulting in a wide range of responses, including interaction with cell-surface receptors to activate intracellular signalling cascades, and intracellular protein/miRNA functioning in recipient cells. It is well established that trophoblast cells release exosomes into the mother?s bloodstream, enabling communication with her immune cells. However, we have recently demonstrated that that this communication is a two-way process; that a) exosomes released by maternal macrophages traffic to trophoblast; and b) macrophage exosomes induce trophoblast cytokine responses. Thus, we hypothesize exosomes facilitate two-way dialogue between the maternal immune system and the trophoblast, which modifies trophoblast function. This could have huge implications for our understanding of regulation of trophoblast differentiation and function, particularly through transfer of functional protein and miRNA exosome cargoes. We have established a multidisciplinary group which encompasses specific expertise in maternal/fetal health, trophoblast immunology, placental macrophage biology, exosome biology and omics analysis. Using a range of primary human tissue/cells from across gestation, our primary objectives are to: 1) investigate trafficking of monocyte/macrophage exosomes, and their cargo, to trophoblast; 2) determine the functional impact of these exosomes on trophoblast differentiation and function in the context of normal pregnancy, and in maternal inflammation; 3) determine the role of specific exosome proteins and miRNAs in exosome-mediated trophoblast differentiation and function. Our findings will broaden our understanding of how maternal immune cells interact with trophoblast cells. We will contribute knowledge as to how trophoblast differentiation and function is regulated by interactions with maternal and placental immune cells, and how dysregulation of this interaction may result in perturbation of normal trophoblast differentiation and function, contributing to pregnancy complications.

Public Health Relevance

Our studies will advance our understanding of how immune cells interact with placental cells- via exosomes- to aid normal placental development and function. We will determine how this interaction is disturbed in maternal inflammation, and therefore how immune cell exosomes mediate placental dysfunction in pregnancy complications such as preterm birth. This research will illuminate new a mechanism for maternal-trophoblast interactions, and thus potential new diagnostics and therapeutic strategies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ilekis, John V
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U of L Imperial Col of Sci/Technlgy/Med
United Kingdom
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