Supervisors: Dr Michelle Oyen and Professor Graham Burton
In human early pregnancy, fetal trophoblast cells invade deeply into the mucosal lining of the uterus, where they transform spiral arteries to ensure the enhanced delivery of blood and nutrients to the developing fetus. Insufficient trophoblast invasion is the underlying pathogenesis of common pregnancy disorders such as pre-eclampsia, fetal growth restriction and recurrent miscarriage. Modelling human trophoblast invasion in vitro has been difficult. Conventional invasion assays require a large number of cells and fail to mimic the conditions found in vivo. We have established the first microfluidic device to study the factors regulating human trophoblast invasion. Small numbers of cells and reagents are needed, chemical gradients and interstitial flow can be precisely controlled, and cell invasion can be observed in real-time. Preliminary studies in the microfluidic device revealed the migration towards a gradient of granulocyte-macrophage colony-stimulating factor (GM-CSF). This novel invasion assay provides a powerful tool enabling important progress to be made in the understanding of human trophoblast cell invasion. The project will dissect the molecular mechanisms regulating trophoblast invasion, focussing initially on the expression and processing of the matrix metalloproteinase enzymes. It will then explore how these may be affected by different stimuli that have been implicated in influencing invasion in vivo, including maternal hormones and pro-inflammatory cytokines. Hence, the project will provide valuable insights into the processes involved in the establishment of a normal pregnancy.
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