Critical signalling pathways in trophoblast invasion

Physiological invasion of human placental trophoblasts into uterine tissues of the pregnant mother is crucial for embryonic development. Whereas shallow invasion and impaired remodelling of uterine spiral arteries is linked to the pathogenesis of the maternal hypertensive disorder preeclampsia and to fetal growth retardation, excessive proliferation and invasion occurs in mole gestations and choriocarcinomas suggesting that accurate control of the process is essential for embryonic survival and wellbeing of the mother. Despite these facts the molecular processes involved remain largely obscure. Here, we propose to utilize different molecular techniques and primary as well as permanent trophoblast cell models to investigate regulatory factors and signalling cascades which we identified by genome-wide mRNA expression profiling of invasive trophoblasts. In detail, the Notch signal transduction pathway crucially involved in development and its downstream effector, the transcriptional regulator suppressor of hairless, will be investigated. In addition, poorly established techniques for primary trophoblasts, i.e. lentiviral- mediated gene transduction and gene silencing will be improved in due course. In summary, the project will give insights into the critical steps of trophoblast cell invasion, thus providing the basis to a better understanding of pregnancy-related diseases.

The aim of the project was to gain more insights into the molecular mechanisms controlling human placental development. In particular, the role of critical signalling pathways controlling invasion of the placental trophoblasts were investigated. The invasive trophoblast migrates into the maternal uterus thereby contributing to the remodelling of the uterine spiral arteries. Dilation of these vessels by invasive trophoblasts and other uterine cell types ensures a constant, low pressure blood flow to the placenta and hence to the developing embryo. Failures in the differentiation program of invasive trophoblasts and vessel remodelling contribute to the pathogenesis of severe gestational diseases, for example intrauterine growth restriction (IUGR) of the fetus or preeclampsia, a high blood pressure disorder of the mother. However, critical steps of human placental development are largely unknown. Similarly, abnormal differentiation and function of invasive trophoblast and its role in the pathogenesis and manifestation of pregnancy diseases have been poorly elucidated. Along those lines, preeclampsia or IUGR also program the fetus to develop diseases during adult life such as hypertensive disorders and cardiovascular problems. Therefore, it is of considerable interest to improve our understanding of normal and pathological placental development and trophoblast invasion. In this project we investigated several signalling pathways controlling human placental development, function and trophoblast invasion. In particular, a main part of the project was to study the role of Notch signalling, which is known to play major roles in human development and also during cancerogenesis. The present data show that trophoblast progenitors in the human placenta produce diverse Notch receptors which could be required for their balanced growth and differentiation towards invasive trophoblasts. In addition, signalling pathways known to be activated during inflammation and upon survival of cells were studied in the context of trophoblast invasion. In summary, results obtained in this project contribute to our understanding of physiological trophoblast invasion. In addition, by characterising Notch signalling, new insight in the function of human trophoblast progenitors were obtained, which could provide the basis for cultivating these cells in vitro and to develop improved model systems for normal and abnormal placental development and trophoblast differentiation.