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“Mini-Placentas” Shine Light on the Cause of Pre-Eclampsia

Trophoblast cells are invading out of the organoid, mimicking placental cells invading the uterus in the early weeks of pregnancy.
Credit: Friedrich Miescher Institute/University of Cambridge.
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Pre-eclampsia is a life-threatening pregnancy complication that affects 2-10% of all pregnancies worldwide. It causes high-blood pressure at around 20 weeks gestation that can lead to serious adverse effects if left untreated.

With the incidence of pre-eclampsia slowly creeping up, researchers from the University of Cambridge have developed a new way to study this condition as outlined in their paper published in Cell Stem Cell.

The difficulties of studying pregnancy complications

The first few weeks of gestation are crucial for a healthy pregnancy. The placenta implants into the endometrium leading to a cascade of cellular interactions at the maternal-fetal interface. Specifically, these interactions play a vital role in enhancing maternal blood supply to the placenta, a necessity for the development of a healthy fetus. Pregnancy complications can arise, including pre-eclampsia, when problems occur with these initial cellular interactions.

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“Most of the major disorders of pregnancy – pre-eclampsia, still birth and growth restriction, for example – depend on failings in the way the placenta develops in the first few weeks. This is a process that is incredibly difficult to study – the period after implantation, when the placenta embeds itself into the endometrium, is often described as a ‘black box of human development’,” said corresponding author Professor Ashley Moffett from the Department of Pathology at the University of Cambridge.

Unfortunately, studying pregnancy complications in the past has proved difficult due to the nature of the subject. Moffett and her team have shown that “mini-placentas” can provide an alternative to observing specimens when studying these conditions. This model allows researchers to experiment on a developing human placenta to investigate the major disorders of pregnancy.

A cellular model of the early stages of the placenta

Many researchers have developed embryo-like models to understand early pre-implantation already, however, our understanding of the cellular interactions between the uterus and the placenta is lacking. The “mini-placentas” known as trophoblast organoids are grown from placenta cells. The experimental model provides insight into early pregnancy and has even been shown to record a positive response on an over-the-counter pregnancy test.

Moffett and team previously identified genes that increase the risk of or protect against several pregnancy conditions. They discovered immune cells found specifically in the uterus – known as uterine natural killer cells – were incredibly important for regulating the interactions between the endometrium and the cells of the placenta.

The team replicated the conditions of early pregnancy by applying the proteins, secreted by the uterine natural killer cells at the point of implantation, to the organoids. They identified several proteins that were vital for the “mini-placentas” development, suggesting they may be crucial for successful implantation. The researchers also identified genes that regulate blood flow and help implantation.

“If the cells aren’t able to invade properly, the arteries in the womb don’t open up and so the placenta – and therefore the baby – are starved of nutrients and oxygen. That's why you get problems later on in pregnancy, when there just isn't enough blood to feed the baby and it either dies or is very tiny,” said Moffett.

The future of pregnancy research

Despite being such a prevalent pregnancy complication, our understanding of how and why pre-eclampsia develops is still limited. The trophoblast organoids offer hope in developing this area of research further.

“Women usually present with pre-eclampsia at the end of pregnancy, but really to understand it – to predict it and prevent it – we have to look at what's happening in the first few weeks,” author Dr. Margherita Turco, from the Friedrich Miescher Institute in Switzerland commented.

“Using ‘mini-placentas’, we can do just that, providing clues as to how and why pre-eclampsia occurs. This has helped us unpick some of the key processes that we should now focus on far more. It shows the power of basic science in helping us understand our fundamental biology, something that we hope will one day make a major difference to the health of mothers and their babies,” she continued.

Reference: Li, Q et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell; 2024; doi: 10.1016/j.stem.2023.12.013

This article is a rework of a press release issued by the University of Cambridge. Material has been edited for length and content.