Human placental development and the uterine microenvironment
Every year, over 300,000 women die from preventable complications occurring during pregnancy and childbirth, and children who survive complicated pregnancies are likely to be faced with life-long developmental challenges. The underlying primary cause of pre-eclampsia, together with fetal growth restriction and stillbirth, collectively termed the Great Obstetric Syndromes (GOS), is abnormal development of the placenta. The placenta is formed by the fetus and is responsible for its nourishment and protection. Despite significant advances in obstetrics and placental biology over the last few years, there are few treatment options available. Thus, there is a great need to unravel the cellular and molecular mechanisms underlying the first stages of placental development to understand what goes awry in pregnancy complications. It is not just during pregnancy that disordered placentation has a translational impact. Sub-optimal placental development is associated with increased susceptibility later in life to cardiovascular and metabolic diseases. This is known as “developmental programming” and results from altered development of fetal organs during the intrauterine period.
The development of the placenta is intimately associated with the endometrium, the lining of the uterus. Proper endometrial growth and differentiation is crucial for a successful pregnancy as there must be an efficient dialogue between these two organs which together constitute the maternal (endometrium) - fetal (placenta) interface. How can we identify and distinguish between the placental and maternal defects that contribute to pregnancy disorders? Studying this has been challenging due to the lack of physiologically relevant in vitro models of human endometrium and placenta.
We have recently developed 3D culture systems (organoids) of human endometrium (Turco et al., Nature Cell Biology 2017) and placenta (Turco et al., Nature 2018) which show remarkable phenotypical and functional similarities to their tissue of origin. These organoids can be expanded and cultured long term and contain both stem cells and differentiated cells. Using these 3D culture systems, our lab aims to unravel the basic biological processes underlying the proliferation and differentiation of these two organs.
1. How are the specialized trophoblast cells generated during the development of the human placenta?
The implanting blastocyst is surrounded by trophectoderm that, after embedding in the endometrium, rapidly develops into an inner layer of highly proliferative trophoblast cells which differentiates two ways: an overlying syncytium (syncytiotrophoblast, SCT) or extravillous trophoblast (EVT) cells that invade into the decidua, the gestational endometrium. Pre-eclampsia and the other GOS are caused by aberrant placentation due to defective differentiation and invasion of the EVT but the underlying mechanisms responsible for this aberrant growth and development of the placenta are still unknown. We aim to unravel the basic developmental processes governing proliferation and differentiation of trophoblast cells.
2. How does the endometrium regenerate every month in preparation for pregnancy?
The endometrium cycles of proliferation, differentiation and shedding is controlled by ovarian hormones. The nature of the stem cell in this dynamic epithelial surface as well as the mechanisms governing its differentiation into the ciliated or secretory lineages, is unknown. This is crucial to understanding normal tissue homeostasis and how this changes in disease. We aim to identify the stem cells within the human endometrium and how tissue homeostasis is affected in various endometrial pathologies such as infertility and hyperplasia.
3. How does the endometrium signal to the placenta in health and disease?
Endometrial glands deliver their secretions into the developing placenta before the haemochorial placenta is established around 10 weeks. This phase of histotrophic nutrition creates a microenvironment that stimulates the proliferation and differentiation of the placenta to ultimately support the embryo during the critical phase of organogenesis. The exact nature of the secretions from endometrial glands and their effect on trophoblast is still largely unknown. Using our endometrial and trophoblast organoid cultures, we aim to understand this maternal-fetal dialogue occurring during early pregnancy. This work is in collaboration with Prof. Graham Burton at the Centre for Trophoblast Research, University of Cambridge.