Characterization of the endothelial cells response to trophoblast debris

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dc.contributor.advisor Chamley, L en
dc.contributor.advisor Chen, Q en
dc.contributor.advisor James, J en
dc.contributor.advisor Blenkiron, C en
dc.contributor.author Wei, Jia en
dc.date.accessioned 2017-05-01T21:20:10Z en
dc.date.issued 2017 en
dc.identifier.uri http://hdl.handle.net/2292/32724 en
dc.description.abstract During pregnancy, the human placenta constantly extrudes extracellular vesicles into the maternal circulation. This deportation of placental extracellular material creates an extensive feto-maternal interface dispersed around the maternal body and exposes various maternal cells to a large amount of fetal/placental material. Preeclampsia, a major complication of pregnancy, is characterized by systemic maternal endothelial cell dysfunction and exaggerated inflammation. It is hypothesized that substances, including placental extracellular vesicles, released from preeclamptic placenta contribute to the pathology of maternal endothelial cell dysfunction. However, how endothelial cells respond to placental extracellular vesicles during normal and preeclamptic pregnancies is not fully elucidated. This work investigated the interaction of endothelial cells with normotensive and preeclamptic trophoblast debris, the largest class of placental extracellular vesicles. The investigations consisted of recognition mechanisms, changes in molecular phenotypes and cellular function of endothelial cells, with the aim of gaining a better understanding of how the maternal vascular system adapts during normal and preeclamptic pregnancies. In this work, it was shown that the protein cargo, IL-1β, in necrotic/ preeclamptic trophoblast debris might directly activate endothelial cells. Trophoblast debris derived from the healthy first trimester placenta could contribute to inflammatory, angiogenic, endocrine and anti-apoptotic responses in endothelial cells by both transcriptomic and functional studies. More importantly, this work showed that trophoblast debris can mediate feto-maternal signalling through modulation of the gene expression in maternal cells rather than simply delivery of messenger RNA. Here it suggested that trophoblast debris travelling through the maternal circulation might contribute to physiological maternal adaptations to pregnancy via the effects on endothelial cells and possibly other cell types. By employing high throughput small RNA sequencing, different small RNA cargos contained within preeclamptic and normotensive trophoblast debris were identified. These small RNA cargos, carried by trophoblast debris, could be directly transferred into maternal recipient cells and thereafter modulate their gene expression. On the other hand, dysregulated small RNAs contained within preeclamptic trophoblast debris is likely to contribute to endothelial cell dysfunction as shown by artificially engineered normotensive trophoblast debris containing excessive miR-145. This engineered debris was able to partially mimic the effect of preeclamptic trophoblast debris on endothelial cell gene expression. Finally, transcriptomic analysis of endothelial cells after exposure to preeclamptic trophoblast debris suggested that these endothelial cells might undergo a DNA-damage response, possibly due to the excessive ROS generation in endothelial cells induced by preeclamptic trophoblast debris. In conclusion, this work has shown that instead of being a waste product of trophoblast turnover, trophoblast debris can convey signals from the feto-placental unit to maternal cells and may contribute to maternal vascular adaptations to pregnancy. However, trophoblast debris can also play a role in systemic endothelial cell dysfunction during preeclampsia, possibly mediated by the dysregulated protein and nucleic acid cargos carried by the debris. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99264931811602091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ en
dc.title Characterization of the endothelial cells response to trophoblast debris en
dc.type Thesis en
thesis.degree.discipline Obstetrics and Gynaecology en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.elements-id 623947 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Molecular Medicine en
pubs.org-id School of Medicine en
pubs.org-id Obstetrics and Gynaecology en
pubs.record-created-at-source-date 2017-05-02 en


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