Maternal-fetal crosstalk during early human pregnancy

In the first days of human development, cells from the fertilized egg, the blastocyst, specialize to give either rise to the fetus or to the placenta. As the human placenta develops, a highly branched, tree- like organ is formed that attaches to the maternal uterine layers and represents the connecting organ between the mother and the fetus. Epithelial cells from the placenta, so-called trophoblasts produce hormones and manage the transport of nutrients, gases, and waste products between the mother and the growing baby. Furthermore, a specialized cell type, the extravillous trophoblast (EVTs) communicates with maternal uterine cells in order to adapt the mother to the ongoing pregnancy. It is important to know that failures in EVT development and function have been causatively linked with gestational complications including preeclampsia, hyper-invasive disorders, and recurrent pregnancy loss. In early placental development, EVTs arise at branching tips, differentiate and invade into the maternal uterine epithelium (the decidua). Their main task comprises the communication with maternal cells such as stromal and immune cells, and the infiltration of maternal luminal structures including arterioles, venules, and uterine glands. Early in pregnancy, before the maternal blood flow to the placenta is established, fetal and placental nutrition is supposedly provided by gland secretions, the so-called uterine milk. EVT infiltration into these structures is considered to support the access to the uterine milk ensuring fetal and placental wellbeing in the first weeks of gestation. While changes in decidual cells are well documented, maternal effects on EVT maturation and function are largely elusive. Studies in regulatory mechanisms orchestrating EVT differentiation were long hampered by inadequate in vitro models. In 2018 we developed conditions to grow 3-dimensional trophoblast organoids (miniature placentae) suitable for studying in vitro formation and differentiation of EVTs. However, we rapidly revealed differences between in vitro organoid-derived EVTs to their in vivo counterparts. It can therefore be concluded that maternal cells contribute to complete EVT maturation. In a first approach we aim to specifically investigate the effects of interactions between decidual stromal cells and EVTs in our 3D organoid model. In our second aim we will use a 3D gland organoid model to investigate modes of communication and gland infiltration by EVTs. In summary we aim to shed light into EVT maturation depending on the interaction with maternal cells in early gestation.