Periodic Reporting for period 3 - HumanPlacenta (Human Placental Development and the Uterine Microenvironment)
Période du rapport: 2023-03-01 au 2024-08-31
The central question I want to address is: how does the human placenta develop, and how is this process influenced by the maternal uterine microenvironment? The placenta is a fetal organ that protects and nourishes the baby during its life in utero and in humans, it grows deeply embedded in the lining of the uterus (decidua). Despite significant advances in obstetrics and placental biology over the last few years, disorders of pregnancy occur frequently and there are few treatment options available, resulting in considerable maternal and/or infant mortality and morbidity. The cause of major pregnancy disorders is abnormal placental development occurring in the first few weeks but ethically and practically this is hard to investigate. The key event for the success of a pregnancy is when placental extravillous trophoblast cells (EVT) invade the spiral arteries of the decidua to access the mother’s blood supply. 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 also due to the lack of 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 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 a bioengineered model of decidua seeded with stromal, glandular and immune cells. 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.
The work achieved for this project during this reporting period is the generation of a detailed database of all the cell types present in the human non-pregnant endometrium, the maternal-fetal interface during early pregnancy and corresponding organoid culture systems using methods that reveals the gene signatures of the cells: (i) single cell RNA sequencing that allows to profile the gene expression of each cell and (ii) spatial transcriptomics that reveals gene signatures of small groups of cells while retaining the information on their localization within the tissue. Obtaining information on the types of cells present in the tissue and their signatures, is essential for several reasons. Firstly, it allows us to understand the signalling that may be critical for the identity of specific cell types. This means that we can now test the role of these identified pathways in the differentiation towards extravillous trophoblast cells and secretory glandular cells of the endometrium, which are the focus of this project. Secondly, it provides a resource that we are using to compare the more complex models we are developing of the maternal-fetal interface.
In the next phase of this project, we will focus our effort on several fronts. Firstly, we will investigate on the fetal side, the role of several genes that we identified in the specialized extravillous trophoblast cells (EVT) of the placenta that may be important for their proper differentiation and function. We will also analyse on the maternal side, the decidual gland cells and their secreted products to understand how these may affect placental development. Lastly, we will then combine the maternal and fetal sides in a bioengineering approach using the organoids to study their interactions. This will allow us to investigate the critical maternal-fetal dialogue occurring during early placentation that are important for pregnancy success.