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Origin and lineage specification of trophoblast cells in early human placenta

Final Report Summary - HTSCS IN PLACENTA (Origin and lineage specification of trophoblast cells in early human placenta)

Pregnancy complications represent a major challenge for women’s health worldwide. 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. There are more than 2.6 million stillbirths per annum worldwide and more than 50,000 maternal deaths to pre-eclampsia, a dangerous hypertensive condition. The underlying cause of miscarriage, pre-eclampsia, fetal growth restriction and stillbirth, collectively termed as Great Obstetric Syndromes, is abnormal placental development. The placenta is the organ that is responsible for nourishing and protecting the developing conceptus during its life in utero.

In order to investigate what goes awry in pregnancy complications we must first understand how human placentation works. This has ethical limitations and without useful in vitro tools to study placental development, our knowledge remains limited. There are many fundamental differences in the most useful animal model, the mouse, in terms of placental anatomy, length of gestation and cell types present. Developing in vitro models that are truly representative of trophoblast, the building blocks of the placenta, is essential to be able to investigate the basic biology of the human placenta. I have taken an interdisciplinary approach to first characterize the proliferative trophoblast population from human placentas in order to reach the aim of this project that is to develop a 3D culture system of the human placenta that accurately represents the tissue in vivo. This will allow us to study processes governing proliferation and differentiation of the human placenta.

It is not just during pregnancy and parturition that disordered placentation has a translational impact. There is an important relationship between sub-optimal placental development and increased susceptibility later in life to health problems such as cardiovascular and metabolic diseases and certain cancers. This phenomenon, “developmental programming” occurs by “programming” fetal organs by influencing the fetal endocrine, cardiovascular and metabolic systems during the intrauterine period. A baby’s birth weight is obviously dependent on the efficient function of the placenta to transport nutrients from the mother, highlighting the importance of the placenta as a key determinant in fetal development and health. Thus, there is a great need to unravel the cellular and molecular mechanisms underlying the first stages of placental development and to develop relevant in vitro models in order to address clinically relevant questions. The proposed study aims to address one of the central questions in placental biology that remain unanswered: “How do the different placental trophoblast populations arise?” This project will generate knowledge that will have profound implications in the placental community and will open doors for further studies.
The main aim of this project ‘Human trophoblast stem cell (hTSCs) in Placenta’ was to address the need to understand human placental development by characterizing the human placenta at a molecular and protein level, and to develop an in vitro culture system to study its function. This proposal has arisen from preliminary results obtained working in the Centre for Trophoblast Research, University of Cambridge. I worked with three Principal Investigators who have many years of experience in placental research: Prof. Ashley Moffett, Dr. Myriam Hemberger and Prof. Graham Burton who have worked on human trophoblast isolation, mouse trophoblast stem cells and human placental function in vivo, respectively. I am thus in an ideal position to capitalize on this extensive expertise from three different labs together with the other stem cell and placental biology labs in Cambridge. This work will provide an essential tool and knowledge to understand early developmental processes and cell lineage relationships during placentation. It also has important translational impact for women and their babies.

The tools and knowledge generated by this project has numerous translational impacts. For a successful pregnancy, there must be a properly formed placenta but also an effective participation from the maternal side, the endometrium. In other words, there must be a correct and efficient communication between the mother and baby. In fact, there is circumstantial evidence that impaired endometrial function is also associated with miscarriage. Over 70% of karyotypically normal embryos miscarried display severe morphological defects that is consistent with a deficient supply of micronutrients coming from the mother early on in pregnancy. It is important to be able to identify the placental as well as the maternal defects that contribute to pregnancy disorders. The in vitro tools that have been generated with this project will allow the investigation of contribution of placenta and endometrium to pregnancy across laboratories that work in this research field. The results from this project have now extended into several lines of research leading to new collaborations, which underline the importance of the work carried out with support of Marie Curie IEF. The collaborations now being set up are: Prof. Jan Brosens (University of Warwick) to study miscarriage; Dr. Nikolaos Polydoropoulos (Bourne Hall Clinic, Cambridge) to study endometrial function and fertility; and Dr. Robin Crawford (University Hospital of Cambridge, Addenbrookes) to study endometrial carcinoma.