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New Study Comprehensively Maps Placental Development in Unprecedented Detail

In a recent study published in Nature, researchers have mapped placental development from start to finish. They used single-cell, spatial-omics, and multi-omics approaches to create an in-depth, high-resolution picture of how the placenta develops and communicates with the uterus. The research team from the Wellcome Sanger Institute, the University of Cambridge, The Friedrich Miescher Institute for Biomedical Research (FMI), Switzerland, EMBL’s European Bioinformatics Institute (EMBL-EBI), and collaborators conducted this study as part of the international Human Cell Atlas (HCA) consortium, which aims to map every cell type in the human body.

Understanding the placenta

The placenta is a temporary organ created by the foetus which facilitates important functions such as foetal nutrition, oxygen and gas exchange, and protects against infections. The formation and embedding of the placenta into the uterus, known as placentation, is essential for a successful pregnancy.

Understanding normal and disordered placentation at a molecular level can help answer questions about poorly understood disorders that include miscarriages, stillbirth, and pre-eclampsia – which affects up to six per cent of pregnancies in the UK, with severe cases developing in about one to two per cent of pregnancies. Despite pregnancy disorders causing illness and death worldwide, many of the processes in pregnancy are not fully understood. This is partly due to the process of placentation being difficult to study in humans, and while animal studies are useful, they have limitations due to physiological differences.

During its development, the placenta forms tree-like structures that attach to the uterus, and the outer layer of cells (called trophoblast) migrate through the uterine wall, transforming the maternal blood vessels to establish a supply line for oxygen and nutrients. Placentation and successful pregnancy depend on the correct degree of trophoblast invasion, and the decidua, the mucosal lining of the pregnant uterus, has an important role in this process.

A spatio-temporal map of placentation

Scientists from the Wellcome Sanger Institute and collaborating institutions have used advanced genomic technologies to examine the process of placental development in unprecedented detail. The team studied a unique historical set of samples of first-trimester pregnant hysterectomies collected over 30 years ago, which include the entire uterus containing the placenta, decidua, and myometrium.

Using a spatially resolved single-cell multi-omics approach, the researchers were able to identify all cell types involved in the process of trophoblast differentiation and how they communicate with the maternal uterine environment around them. The findings describe the involvement of multiple populations of cells, such as maternal immune and vascular cells, potentially explaining the disease process.

The team used a statistical framework to describe the complete trophoblast invasion trajectory during the first trimester of pregnancy. They also used this approach to benchmark current in vitro trophoblast models, including trophoblast stem cells and self-renewing primary trophoblast organoids, and demonstrate that they faithfully recapitulate extravillous trophoblast EVT differentiation. However, the study found that these models lack terminal EVTs and deep invasive glandular cells, which are present only in the uterus and require maternal signals from uterine cells and maternal serum to generate them.

The team focused on the role of macrophages and predicted the ligand-receptor interactions between these cells and EVTs, and pinpointed the potential molecular and cellular mediators of arterial transformation during early pregnancy. The study also identified novel interactions between trophoblasts and endothelial cells that enable EVTs to adhere to them.

Implications and future directions

This new understanding of the trophoblast landscape at the implantation site can facilitate the development of effective lab models to study placental development and may lead to new ways to diagnose, prevent, and treat pregnancy disorders. The insights gained from this research may also help researchers understand the causes of pregnancy complications such as pre-eclampsia, a potentially life-threatening condition that can occur in the second half of pregnancy.

Moreover, the study highlights the importance of addressing women’s health issues, which are often overlooked. Pregnancy is a unique period in a woman’s life that requires specialized medical attention, and any deviations from normal placental development can have long-term health consequences for both the mother and child. Unfortunately, women’s health issues are frequently dismissed or downplayed, leading to inadequate care and poorer outcomes.

By shedding light on the mechanisms that govern placental development, this study provides valuable insights that can inform clinical practice and ultimately improve maternal and foetal health outcomes. It also underscores the importance of prioritizing women’s health and ensuring that they receive the care and attention they need throughout pregnancy and beyond.