Over the course of this project, we made several major findings that advance our understanding of human placental development and its interaction with the maternal uterus.
Firstly, we generated one of the first detailed maps of the cells that make up the human uterine lining before pregnancy and the maternal-fetal interface in early pregnancy. In parallel, we systematically compared placental and uterine organoid models to their tissues of origin to assess how accurately they reflect their biology. To achieve this, we used advanced technologies that measure gene activity in individual cells while preserving their spatial organisation within tissues. This allowed us to identify the different cell types present, determine where they are located, and understand how they change as they develop into specialised cell types. In particular, we focused on invasive placental cells (extravillous trophoblast), which enter the uterus to establish the blood supply required for fetal development, a process that had not previously been characterised at this level of detail in humans. Importantly, we found that these organoid models faithfully reproduce key features of the original human tissues. Together, these advances provide a unique resources to study early human pregnancy and establish a foundation for investigating interactions between maternal and fetal tissues.
Secondly, we not only defined the cell types present at the maternal-fetal interface but also began to understand how they communicate with each other. We identified key signals exchanged between maternal and placental cells that regulate placental development and invasion. We then tested these signals experimentally, focusing on interactions between placental cells and maternal cell types, including glandular cells and uterine natural killer cells. Using an image-based screening approach, we found that factors produced by maternal immune cells, particularly uterine natural killer cells, promote the development and invasive behaviour of placental cells. This demonstrates an active role of the mother in regulating placental development.
Thirdly, we developed bioengineered models that combine placental and uterine organoids to recreate key aspects of the maternal-fetal interface. These systems allow us for the first time, to experimentally investigate how maternal and fetal tissues interact in a controlled human setting and to identify the signals exchanged between them.
Overall, this work provides both a reference map of human uterine and placental cell types and experimental systems to study their interactions. By moving from describing tissues to experimentally testing how they communicate, the project represents a significant advance in understanding early human pregnancy and the origins of pregnancy disorders.
