29/11/2018
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Researchers say that new ‘mini-placentas’ – a cellular model of the early stages of the placenta – could provide a window into early pregnancy and help transform our understanding of reproductive disorders. Details of this new research are published today in the journal Nature. Many pregnancies fail because the embryo does not implant correctly into the lining of the womb (uterus) and fails to form a placental attachment to the mother. Yet, because of the complexities of studying this early period of our development, very little is understood about what is happening normally and what can go wrong. Animals are too dissimilar to humans to provide a good model of placental development and implantation, and stem cell studies have largely proved unsuccessful. “The placenta is absolutely essential for supporting the baby as it grows inside the mother,” says Dr Margherita Turco, the study’s first author, from the Departments of Pathology and Physiology, Development and Neuroscience at the University of Cambridge. “When it doesn’t function properly, it can result in serious problems, from pre-eclampsia to miscarriage, with immediate and lifelong consequences for both mother and child. But our knowledge of this important organ is very limited because of a lack of good experimental models.” Efforts to grow human placental cells started over 30 years ago in the Pathology department where Professors Ashley Moffett and Charlie Loke were studying cellular events in the first few weeks of pregnancy. With their chief technician, Lucy Gardner, they found ways to isolate and characterise placental trophoblast cells. These techniques, combined with the organoid culture system, enabled the generation of miniature functional models of the early placenta – or ‘mini-placentas’. In the past few years, a new field of research has blossomed that uses these organoids – often referred to as ‘mini-organs’ – enabling insights into human biology and disease. At the University of Cambridge, one of the world leaders in organoid research, scientists are using organoid cultures to grow everything from ‘mini-brains’ to ‘mini-livers’ to ‘mini-lungs’. In a study funded by Wellcome and the Centre for Trophoblast Research, the Cambridge team was able to grow organoids using cells from villi – tiny frond-like structures – taken from placental tissue. These trophoblast organoids are able to survive long-term, are genetically stable and organise into villous-like structures that secrete essential proteins and hormones that would affect the mother’s metabolism during the pregnancy. Further analysis, including epigenetic analysis performed by Dr Myriam Hemberger, a group leader at the Babraham Institute and paper co-author, showed that the organoids closely resemble normal first-trimester placentas. In fact, the organoids so closely model the early placenta that they are able to record a positive response on an over-the-counter pregnancy test. Dr Myriam Hemberger, also a Principal Investigator at the Centre for Trophoblast Research, explains: “The organoids appear to closely recapitulate key physiological features of the placenta. As such, they will open many doors into studies investigating the causes of pregnancy complications many of which have their roots in the first few weeks after conception.” Professor Graham Burton, a co-author and Director of the Centre for Trophoblast Research, which last year celebrated its tenth anniversary, says: “These ‘mini-placentas’ build on decades of research and we believe they will transform work in this field. They will play an important role in helping us investigate events that happen during the earliest stages of pregnancy and yet have profound consequences for the life-long health of the mother and her offspring. The placenta supplies all the oxygen and nutrients essential for growth of the fetus, and if it fails to develop properly the pregnancy can sadly end with a low birthweight baby or even a stillbirth.” In addition, the organoids may shed light on other mysteries surrounding the relationships between the placenta, the uterus and the fetus: why, for example, is the placenta able to prevent some infections passing from the mother’s blood to the fetus while others, such as Zika virus, are able to pass through this barrier? The organoids may also be used for screening the safety of drugs to be used in early pregnancy, to understand how chromosomal abnormalities may perturb normal development, and possibly even provide stem cell therapies for failing pregnancies. Last year, the same team supported by Cambridge’s Centre for Trophoblast Research reported growing miniature functional models of the uterine lining. “Now that we’ve developed organoid models of both sides of the interface – maternal tissue and placental tissue – we can start to look at how these two sides talk to each other,” adds Professor Ashley Moffett. Professor Moffett also co-directed a recent study published in Nature that used genomics and bioinformatics approaches to map over 70,000 single cells at the junction of the uterus and placenta. This study revealed how the cells talk to each other to modify the immune response and enable the pregnancy, presenting new and unexpected cell states in the uterus and placenta, and showing which genes are switched on in each cell. Notes for Editors
This news item is adapted from a media release from the University of Cambridge. Publication reference Turco, MY et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature; 28 Nov 2018; DOI:10.1038/s41586-018-0753-3 Contact details Craig Brierley Head of Research Communications University of Cambridge Tel: +44 (0)1223 766205 / Mob: +44 (0)7957 468218 Email: craig.brierley@admin.cam.ac.uk Image description: The cultured organoids produce the same hormones as the early placenta and are able to record a positive response on an over-the-counter pregnancy test. Trophoblast organoid supernatants were tested with Clear&Simple Digital Pregnancy Test. Image reproduced with the permission of SPD Swiss Precision Diagnostics GmbH (SPD).
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Affiliated authors: Dr Myriam Hemberger, Group Leader, Epigenetics research programme About the University of Cambridge The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 107 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of the ‘Cambridge cluster’, which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents. www.cam.ac.uk About the Babraham Institute The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
29 November 2018