The Role of miR-218-5p and TGF-B Signaling in Human Placenta from Normal and Comprised Pregnancies
| dc.contributor.advisor | Peng, Chun | |
| dc.creator | Brkic, Jelena | |
| dc.date.accessioned | 2017-07-27T13:35:49Z | |
| dc.date.available | 2017-07-27T13:35:49Z | |
| dc.date.copyright | 2017-01-18 | |
| dc.date.issued | 2017-07-27 | |
| dc.date.updated | 2017-07-27T13:35:48Z | |
| dc.degree.discipline | Biology | |
| dc.degree.level | Doctoral | |
| dc.degree.name | PhD - Doctor of Philosophy | |
| dc.description.abstract | Placenta is critical during pregnancy, forming the interface between mother and fetus. A key process in placental development is the differentiation and invasion of extravillous trophoblast cells (EVT). While some EVT invade the uterine interstitial space, a subset upregulates endovascular genes forming the endovascular EVT (enEVT) that invade decidual vessels. EnEVT are critical mediators in spiral artery remodeling (SAR), which is essential for proper placentation. Preeclampsia (PE) is a serious hypertensive disorder that can manifest during pregnancy. The cause of PE is unclear; however shallow EVT invasion, inadequate enEVT differentiation and SAR play crucial roles. The transforming growth factor- (TGF-) family is known to regulate placentation and has been implicated in the pathogenesis of PE. Specifically, TGF-s and Nodal are upregulated in PE placenta and they exert potent inhibitory effects on EVT invasion. MicroRNAs (miRNA) are small non-coding RNAs that regulate most physiological processes and are dysregulated in PE. In this study, we investigated the role of miR-218-5p in modulating TGF- signaling and placental development and their contribution to the pathogenesis of PE. The models used in our study included a human trophoblast cell line (HTR8/SVneo), first trimester placenta and decidua tissues, and clinical samples. Our findings indicate that the expression of miR-218-5p was downregulated in PE and upregulated during second trimester in healthy tissues. Overexpression of miR-218-5p promoted trophoblast migration and invasion. Furthermore, miR-218-5p upregulated key genes involved in enEVT differentiation and accelerated SAR in vitro. Using a TGF- signaling reporter, we found that basal and TGF--induced transcriptional activities were strongly inhibited by mir-218-1. TGF-2, Smad2, and Smad3 are predicted miR-218-5p targets, and their expression was inhibited by miR-218-5p. Both TGF-2 and Smad2 were able to partly rescue the miR-218-5p phenotype. Interestingly, knockdown of Smad2 promoted, while knockdown of Smad3 inhibited, invasion and enEVT differentiation, suggesting they play differential roles in placentation. Additionally, the level of pSmad3 is strikingly downregulated in PE placentas. In conclusion, our study demonstrates that TGF- signaling in the maternal-fetal interface is modulated by miR-218-5p and disruption of the balance between miR-218-5p and TGF- signaling may lead to abnormal placental development and pregnancy complications. | |
| dc.identifier.uri | http://hdl.handle.net/10315/33520 | |
| dc.language.iso | en | |
| dc.rights | Author owns copyright, except where explicitly noted. Please contact the author directly with licensing requests. | |
| dc.subject | Pathology | |
| dc.subject.keywords | Biology | |
| dc.subject.keywords | Molecular biology | |
| dc.subject.keywords | Pathology | |
| dc.subject.keywords | Placenta | |
| dc.subject.keywords | Preeclampsia | |
| dc.subject.keywords | Trophoblasts | |
| dc.subject.keywords | MicroRNA | |
| dc.subject.keywords | TGF-beta | |
| dc.subject.keywords | Gestational disease | |
| dc.subject.keywords | Endovascular trophoblast | |
| dc.subject.keywords | Spiral artery remodelling | |
| dc.subject.keywords | Smad2 | |
| dc.subject.keywords | Smad3 | |
| dc.title | The Role of miR-218-5p and TGF-B Signaling in Human Placenta from Normal and Comprised Pregnancies | |
| dc.type | Electronic Thesis or Dissertation |
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