Project description
Development of human placenta
Pregnancy depends on the early stages of development when placental extravillous trophoblast cells (EVTs) infiltrate the uterine mucosa, the decidua. EVTs invade the decidua to transform the uterine spiral arteries into dilated vessels. Understanding the molecular and cellular mechanisms of maternal-foetal interactions has been challenging due to the lack of reliable in vitro models. The focus of the EU-funded HumanPlacenta project is on how the human placenta develops and in what way it depends on the maternal uterine microenvironment. Researchers will employ recently derived 3D culture organoids from human decidua and placenta. Using these organoids for single-cell genomics, CRISPR/Cas9 editing and tissue engineering studies will elucidate the mechanisms that specify the EVT lineage, the role of paracrine signalling in regulating placental development, and cell-cell interactions between decidua and EVTs.
Objective
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.
Fields of science
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologytissue engineering
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesclinical medicineobstetricsfetal medicine
- medical and health sciencesclinical medicineembryology
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
4056 BASEL
Switzerland