Human Placental Development and the Uterine Microenvironment

ended

How does the human placenta develop and how is this influenced by the maternal uterine microenvironment? These are the central questions addressed in my proposal. Normal growth and development of the fetus depends on the placenta, the extra-embryonic organ derived from trophectoderm. Successful pregnancy depends on the earliest stages of development when placental extravillous trophoblast cells (EVT) infiltrate the uterine mucosa, the decidua. EVT invade the decidua to transform the uterine spiral arteries into a dilated vessel capable of high conductance. Deficient arterial remodelling by EVT results in miscarriage, pre-eclampsia, fetal growth restriction and stillbirth. However, excessive invasion into the uterine wall is also potentially dangerous. Thus, to achieve a successful pregnancy, a territorial boundary is drawn with a balance between fetal EVT invasion and maternal decidual cells. Understanding the molecular and cellular mechanisms underlying these maternal/fetal interactions has been challenging due both to practical and ethical limitations and lack of reliable in vitro models. I have recently derived 3D culture systems (organoids) from human decidua and placenta that will provide the essential tools. I will use these organoids combined with single cell genomics, Crispr/Cas9 genome editing and tissue engineering to study: (i) the molecular mechanisms that specify the EVT lineage (ii) the role of paracrine signalling from maternal decidual glands in regulating placental development (iii) cell-cell interactions between decidua and EVT by creating an artificial model of decidua made from tailored collagen scaffolds seeded with stromal, glandular and immune cells. My proposal capitalises on the remarkable ability of organoid cultures to faithfully model human physiology. The human uterine environment in early pregnancy is crucial for reproductive success and development of an in vitro model of placentation will have a wide-ranging impact.