Obstetrics and Gynaecology - Theses
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ItemAgeing of the placenta: potential prognostics, diagnostics and therapeutics( 2022)Abstract Ageing effects on human organs are most notable in the elderly. However, the placenta is exceptional because it shows signs of ageing in a short time span. Healthy ageing of the placenta is the process of developing and maintaining the functional ability of the placenta until term and is a feature of uncomplicated pregnancies. However, recent studies show unhealthy ageing of the placenta is a common feature of important human pregnancy disorders. Unhealthy premature ageing of the placenta is associated with pregnancy complications of preeclampsia (PE) and fetal growth restriction (FGR), whereas unhealthy placental ageing at term is associated with stillbirth. Given the emerging importance of placental ageing, the general aim of the work was to investigate potential prognostics, diagnostics and therapeutics for ageing of the placenta. Regarding prognostics and diagnostics, the sFlt-1/PlGF ratio test used to predict the risk of PE was investigated in a retrospective clinical study. The sFlt-1/PlGF ratio increased with the healthy ageing of the placenta at term. In addition, the total extracellular vesicle population isolated from the maternal peripheral blood during second trimester increased in pregnancies with a late onset PE outcome compared to a gestation matched normotensive control outcome and showed an association with the sFlt-1 concentration. These results suggest that the sFlt-1/PlGF ratio and EV population size are potential prognostic or diagnostic markers for unhealthy placental ageing-associated pathologies such as PE and stillbirth. A hallmark of ageing is damage to stem cells, which prevents them from replenishing cells in ageing organs and tissues. Pharmaceutical drugs and extracellular vesicles (EV) with anti-ageing properties secreted by healthy ageing early term decidual mesenchymal stem cells (ET-DMSC) were used to treat unhealthy premature-ageing PE-DMSC and ageing late term DMSC (LT-DMSC). As well, a microRNA present in high levels in ET-DMSC (miR-516b-5p) was also analysed. Drugs with anti-ageing properties and EV from ET-DMSC delayed the ageing phenotype of both PE-DMSC and LT-DMSC. In addition, miR-516b-5p affected stem cell survival. ET-DMSC with elevated levels of miR-516b-5p had better survivability. Finally, as described above, the total EV population size in maternal blood is a potential prognostic or diagnostic marker for unhealthy placental ageing-associated pathologies. However, many cell types, including stem cells, secrete EV into maternal blood. The final aim was to determine whether EV secreted from DMSC into maternal blood could be enriched from maternal blood. In order to achieve this, unique DMSC-EV cell surface markers need to be identified. When compared with chorionic mesenchymal stem cell derived EV (CMSC-EV), mass spectrometry analyses showed DMSC-EV and CMSC-EV have unique combinations of lipids and proteins on their surface, which could potentially facilitate the isolation of DMSC-EV and CMSC-EV from maternal blood. In addition, studies in the literature showed that changes in the levels of candidate lipids and proteins are associated with healthy ageing and in some cases with unhealthy placental ageing-associates pathologies such as PE and FGR, where the placenta shows signs of premature ageing.