B-101 Placental exosomes in maternal-placental-fetal communication and viral resistance

Abstract

The placenta plays a critical role in regulating maternal-fetal gas exchange, supply of nutrients to the fetus and removal of waste, production of hormones, and immunological defense, including resistance to diverse pathogens. While many of these functions are controlled by hormones, growth factors and other signaling molecules, the recent discovery of placental small RNAs and their release to the plasma within extracellular vesicles provides a new dimension to our investigation into paracrine and distant signaling networks that constitute maternal-fetal crosstalk. In this context, we found that primary human trophoblasts are resistant to infection by diverse types of DNA and RNA viruses, and that this resistance can be partly conferred to non-trophoblastic cells by transferring placenta- and primate-specific miRNAs, expressed from the chromosome 19 miRNA cluster (C19MC). Furthermore, we found that all trophoblastic EVs contain C19MC miRNAs, and that trophoblastic exosomes execute an antiviral effect when applied to non-placental cells. To pursue the patterns of miRNA transport in vivo among the maternal, placental and fetal compartments, we created a humanized mouse model that stably expresses the human C19MC miRNA cluster. We detected the trafficking of placental miRNAs among the maternal and fetal compartments. Our current work centers on the mechanisms of uptake of trophoblastic exosomes by non-trophoblastic cells, and the proteins that are essential for that process. Together, our findings establish previously unrecognized mechanisms of exosome-based maternal-fetal crosstalk. These pathways have functional implications for defense against viral pathogens and possibly have other homeostatic functions during pregnancy.