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The effect and underlying mechanisms of bone morphogenetic protein 2 in regulating human trophoblast cell invasion

University of British Columbia

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-SMAD2/3-SMAD4 signaling; 2) Up-regulating inhibin βA and activin A production via ALK3-BMPR2/ACVR2A-SMAD1/5/8-SMAD4 signaling; 3) Inducing ID1-mediated up-regulation of insulin-like growth factor binding protein 3 (IGFBP3); and 4) Inducing WNT/β-catenin signaling activation mediated by bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI). These findings deepen our understanding of the roles of BMP2 in placentation and provide insights into the molecular mechanisms of human trophoblast invasion.

Text

2020-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/69539

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/