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Ahmed, Faten

University of British Columbia

Placental insufficiency disorders, including preeclampsia (PET), intrauterine growth restriction (IUGR) and preterm labor (PTL), are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes share a common phenomenon of poor placental trophoblast cell invasion into the uterine tissue. To date there are no effective treatments for these illnesses. Placental invasion is controlled by many hormones and growth factors, among which the transforming growth factor (TGF)-β superfamily is a well-known regulator. Myostatin (MSTN) is a TGF-β superfamily member recognized for its important role in muscle growth control. Recently, MSTN was shown to be secreted and functioning in the placenta. In addition, MSTN serum and/or placental levels were found to be upregulated in common pregnancy complications including PET and IUGR. Yet, the role of MSTN in placental biology is poorly understood. In this study, I confirmed the positive effect of MSTN treatment on human trophoblast invasion and performed mRNA sequencing on control and MSTN-treated primary trophoblast cells (n=5). This analysis identified 610 differentially expressed genes (DEGs) with a false discovery rate <0.05, of which 380 were upregulated and 230 genes were downregulated. DEGs were highly enriched in epithelial mesenchymal transition (EMT) genes, among which serine protease inhibitor E2 (SERPINE2), plasminogen activator inhibitor-1 (PAI-1), SRY-Box Transcription Factor 4 (SOX4) and the cell adhesion molecule N-cadherin (N-Cad) were validated using RT-qPCR and Western blot. I then demonstrated that each of those genes was involved in MSTN-induced trophoblast cell invasion. Finally, I investigated the upstream signaling and found that MSTN induced upregulation of SERPINE2, PAI-1 and N-Cad via the canonical ALK4/5-SMAD2/3/4 signaling pathway. iv However, SMAD2 does not appear to be involved in MSTN-induced PAI-1 upregulation. In addition, SOX4 was involved in MSTN-induced SERPINE2 upregulation. Collectively, the current study deciphers the underlying molecular mechanisms involved in MSTN-induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.

Text

2024-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83548

Reproductive and Developmental Sciences

University of British Columbia

UBCV

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