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UBC Theses and Dissertations

Bone morphogenetic protein 2 governs invasive trophoblast functions by regulating extracellular matrix and adhesion molecules at the maternal-fetal interface Yuyin, Yi


Many pregnancy disorders, including pregnancy loss, preeclampsia, preterm birth and intrauterine growth restriction are associated with defects in placental development, including abnormal placental trophoblast invasion and differentiation. Bone morphogenetic protein 2 (BMP2) belongs to the transforming growth factor-β (TGF-β) superfamily and controls various physiological and developmental processes. Previous studies have demonstrated the pro-invasive action of BMP2 signaling in human trophoblasts in vitro. However, the expression of BMP2 in the placenta and underlying molecular mechanisms of how BMP2 regulates trophoblast function remain unclear. In this study, we analyzed several publicly available microarray datasets and revealed that BMP2 was expressed in the placenta across all three trimesters. Importantly, BMP2 levels were significantly reduced in placenta samples from early-onset preeclampsia pregnancies compared with gestational age-matched normal pregnancies. RNAscope in situ hybridization showed that in the first trimester BMP2 was localized in all subtypes of trophoblasts as well as in decidua. To further investigate downstream transcriptional targets of BMP2 signaling, we performed mRNA-sequencing on control and BMP2-treated primary human trophoblasts (n=5). This analysis identified 431 differentially expressed genes, of which 253 were upregulated and 178 were downregulated, with a false discovery rate < 0.05. We found that BMP2 enhances first-trimester placental trophoblast invasion by regulating a network of cellular adhesion and extracellular matrix genes. Furthermore, we identified SOX4 as a direct target gene of BMP2 in trophoblasts. Importantly, SOX4 can transcriptionally regulate the expression of SOX4-dependent BMP2 targets by binding to the regulatory elements such as enhancers, thereby promoting BMP2-induced trophoblast invasion. Lastly, we assessed the effect of BMP2 on gene expression in decidual stromal cells and the resulting regulation of trophoblast invasion by decidual stromal cells. The results suggest BMP2 induces the production of SPON2 by decidual stromal cells, which in turn restricts trophoblast invasion. Collectively, this study demonstrates the association of dysregulated placental BMP2 expression with EOPET and elucidates novel mechanisms of BMP2 action at the first-trimester maternal-fetal interface.

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