Growth differentiation factor myostatin regulates epithelial‐mesenchymal transition genes and enhances invasion by increasing serine protease inhibitors E1 and E2 in human trophoblast cells

Abstract

Placental insufficiency disorders, including preeclampsia and intrauterine growth restriction, are major obstetric complications that can have devastating effects on both the mother and the fetus. These syndromes have underlying poor placental trophoblast cell invasion into uterine tissues. Placental invasion is controlled by many hormones and growth factors. Myostatin (MSTN) is a transforming growth factor‐β superfamily member recognized for its important role in muscle growth control. MSTN has also been shown to be secreted and functioning in the placenta, and its serum and/or placental levels were found to be upregulated in preeclampsia and intrauterine growth restriction. Considering that the mechanistic role of MSTN in placentation remains poorly understood, we hypothesized that MSTN uses ALK4/5‐SMAD2/3/4 signaling to increase human trophoblast invasion through a group of epithelial–mesenchymal transition genes including SERPINE2, PAI‐1, and SOX4. mRNA sequencing of control and MSTN‐treated primary human trophoblast cells (n = 5) yielded a total of 610 differentially expressed genes (false discovery rate <0.05) of which 380 genes were upregulated and 230 were downregulated. These differentially expressed genes were highly enriched in epithelial–mesenchymal transition genes, and a subset including SERPINE2, PAI‐1, and SOX4 was investigated for its role in MSTN‐induced trophoblast cell invasion. We found that MSTN induced upregulation of SERPINE2 via ALK4/5‐SMAD2/3/4 signaling; however, SMAD2 was not involved in MSTN‐induced PAI‐1 upregulation. SOX4 was involved in MSTN‐induced upregulation of SERPINE2, but not PAI‐1. Collectively, this study discovers novel molecular mechanisms of MSTN‐induced human trophoblast cell invasion and provides insight into the functional consequences of its dysregulation in placental insufficiency disorders.

Serpin peptidase inhibitor, clade E, member 2 in physiology and pathology: recent advancements

“…Serpin E2 was also found to be highly expressed in the apical and glandular epithelium of the endometrial lumen in the middle and late secretory phases of the menstrual cycle, but weakly expressed in the proliferative phase of the endometrium. Further, serpin E2 is thought to play a role in embryo implantation, because of its high expression during the secretory phase and can regulate the proteolytic degradation and fibrinolysis of extracellular matrix in endometrial cells, which is crucial for decidualization and trophoblast invasion during implantation, and its function in the human uterus may be related to tissue remodeling regulated by PA ( Lee et al, 2011 ; AbdelHafez et al, 2023 ; Do et al, 2023 ).…”