The role of miR-218-5p and miR-210-3p in human trophoblast function and placenta development

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dc.contributor.advisorPeng, Chun
dc.contributor.authorHayder, Heyam Y.
dc.date.accessioned2022-08-08T15:50:38Z
dc.date.available2022-08-08T15:50:38Z
dc.date.copyright2022-02-15
dc.date.issued2022-08-08
dc.date.updated2022-08-08T15:50:38Z
dc.degree.disciplineBiology
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractMicroRNAs (miRNA) are small non-coding RNAs that primarily regulate gene expression at the post-transcriptional level. Studies have shown that miRNAs play important roles in placenta development and are dysregulated in pregnancy complications such as preeclampsia (PE). One such miRNA is hsa-miR-210-3p, which is upregulated in PE. We found that miR-210-3p overexpression reduced trophoblast migration and invasion and extravillous trophoblast (EVT) outgrowth in first trimester explants. Its overexpression also downregulated endovascular trophoblast (enEVT) markers, the ability of trophoblast to form endothelial-like networks, and the mRNA levels of interleukin-1B and -8 and CXC motif ligand 1. These cytokines play a role in EVT invasion and the recruitment of immune cells to spiral artery remodelling sites. We also showed that caudal-related homeobox transcription factor 2 (CDX2) is a novel target of miR-210-3p and that CDX2 downregulation mimicked the observed effects of miR-210-3p upregulation. These findings suggest that miR-210-3p overexpression impairs spiral artery remodelling, thus contributing to PE pathogenesis. Recently, we reported that hsa-miR-218-5p promotes trophoblast migration, invasion, differentiation down the endovascular pathway, and is downregulated in PE. Through microarray analysis, we identified neuropeptide Y (NPY) as a possible target gene of miR-218-5p. Although NPY is known to be produced by human placenta, little is known about its function during pregnancy. We found that miR-218-5p upregulates NPY pre- and mature mRNA and protein levels. It also targets NPY receptor 1 (NPY1R) mRNA at the 3' UTR, resulting in decreased mRNA levels but not the protein. Using immunohistochemistry, we detected NPY and NPY1R in first trimester placentas. Also, using immortalized EVT cell lines to examine cell proliferation, migration, and invasion, we found that NPY overexpression decreased EVT migration and invasion while silencing it increased their motility and proliferation. NPY effect on motility was attenuated by an NPY1R-specific inhibitor. Meanwhile, NPY1R overexpression decreased EVT proliferation while NPY1R antagonists increased it. Using the floating first-trimester villous model, we found that NPY knockdown or blocking NPY1R signalling increased cytotrophoblast proliferation. These findings suggest that the NPY-NPY1R signalling pathway is a negative regulator of placenta development.
dc.identifier.urihttp://hdl.handle.net/10315/39613
dc.languageen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectBiology
dc.subject.keywordsPlacenta development
dc.subject.keywordsTtrophoblast
dc.subject.keywordsmiRNA
dc.subject.keywordsmiR-210
dc.subject.keywordsCDX2
dc.subject.keywordsInterleukins
dc.subject.keywordsCytokines
dc.subject.keywordsmiR-218
dc.subject.keywordsNPY
dc.subject.keywordsNPY1R
dc.subject.keywordsAngiogenesis
dc.subject.keywordsProliferation
dc.subject.keywordsMotility
dc.titleThe role of miR-218-5p and miR-210-3p in human trophoblast function and placenta development
dc.typeElectronic Thesis or Dissertation

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