The effect and underlying mechanisms of bone morphogenetic protein 2 in regulating human trophoblast cell invasion
department or school: Medicine, Faculty of
department or school: Obstetrics and Gynaecology, Department of
data provider: DSpace
degree campus: UBCV
creator: Zhao, Hongjin
issued: 2020-04-30T07:00:00Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: During placentation, extravillous cytotrophoblasts (EVTs) derived from villous cytotrophoblasts invade into the uterine wall for proper placentation and successful establishment of human pregnancy. Insufficient trophoblast invasion contributes to several pregnancy complications including preeclampsia, which is a leading cause of maternal mortality and affects 2-8% of pregnancies worldwide. As an important member of the transforming growth factor β (TGF-β) superfamily, bone morphogenetic protein 2 (BMP2) is abundantly produced at the maternal-fetal interface and its expression is spatiotemporally correlated with embryo placentation. BMP2 is crucial for endometrial decidualization in humans and normal fertility in mice. In addition, BMP2 exerts pro-invasive effects in a variety of cancer cells. However, whether BMP2 can promote trophoblast cell invasion during placentation remains unknown. BMPs increase mesenchymal adhesion molecule N-cadherin expression, activin A production, an inhibitor of DNA-binding protein 1 (ID1) expression, and WNT/β-catenin signaling in different cell types. All of the above mentioned molecules and signals have been shown to positively regulate human trophoblast or cancer cell invasion, thus we hypothesized that BMP2 could promote human trophoblast cell invasion by regulating the expression of N-cadherin, activin A and ID1 as well as the activation of canonical WNT/β-catenin signaling. Primary and immortalized (HTR8/SVneo) cultures of human EVT cells were used as study models. Activin receptor-like kinase 2/3 (ALK2/3) inhibitor DMH1 and ALK4/5/7 inhibitor SB431542 were used to block receptor-mediated signaling. Small interfering RNA (siRNA) was used to study the involvement of key signaling molecules. Cell invasiveness was examined using the Matrigel-coated transwell invasion assay. Overall, our results demonstrate that BMP2 promotes trophoblast cell invasion via the following mechanisms: 1) Up-regulating N-cadherin via non-canonical ALK2/3/4…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/69539
note: THE EFFECT AND UNDERLYING MECHANISMS OF BONE MORPHOGENETIC PROTEIN 2 IN REGULATING HUMAN TROPHOBLAST CELL INVASION by Hongjin Zhao Bachelor of Medicine, Shandong University, 2008 Master of Medicine, Shandong University, 2010 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Reproductive and Developmental Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2019 © Hongjin Zhao, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: THE EFFECT AND UNDERLYING MECHANISMS OF BONE MORPHOGENETIC PROTEIN 2 IN REGULATING HUMAN TROPHOBLAST CELLS INVASION submitted by Hongjin Zhao in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Reproductive and Developmental Sciences Examining Committee: Dr. Peter C.K. Leung Supervisor Dr. Xuesen Dong Supervisory Committee Member Dr. Dan Rurak Supervisory Committee Member Dr. Alexander Guillermo Beristain University Examiner Dr. Ivan Robert Nabi University Examiner Additional Supervisory Committee Members: Dr. Christian Klausen Supervisory Committee Member Dr. Evica Separovic Supervisory Committee Member iii Abstract During placentation, extravillous cytotrophoblasts (EVTs) derived from villous cytotrophoblasts invade into the uterine wall for proper placentation and successful establishment of human pregnancy. Insufficient trophoblast invasion contributes to several pregnancy complications including preeclampsia, which is a leading cause of maternal mortality and affects 2-8% of pregnancies worldwide. As an important member of the transforming growth factor β (TGF-β) superfamily, bone morphogenetic protein 2 (BMP2) is abundantly produced at the maternal-fetal interface and its expression is spatiotemporally correlated with embryo placentation. BMP2 is crucial for endometrial deci…
has type: Thesis/Dissertation
date issued: 2019-05
is shown at: 10.14288/1.0378056
language: eng
degree discipline: Reproductive and Developmental Sciences
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/69539