Abstract

The motility of endometrial stromal cells (ESCs) contributes to the restoration of the endometrial functional layer and subsequently supports the trophoblast invasion during early pregnancy. Following ESCs differentiation through decidualization in response to progesterone during the menstrual cycle and embryo implantation, decidualized ESCs (D-ESCs) have greater motility and invasive activity. The human proinsulin-connecting peptide (C-peptide) is produced in equimolar amounts during the proteolysis of insulin in pancreatic β-cells. However, the function of C-peptide in the cellular motility of the human endometrium remains unexamined. In the present study, C-peptide was identified as a determinant of undecidualized human endometrial stromal cells (UnD-ESCs) migration. C-peptide promoted the migration and invasion of UnD-ESCs and trophoblast-derived Jeg3 cells, but not that of ESCs post decidualization, a functional and biochemical differentiation of UnD-ESCs. Both Akt and protein phosphatase 1 regulated β-catenin phosphorylation in UnD-ESCs, not D-ESCs, thereby promoting β-catenin nuclear translocation in C-peptide-treated UnD-ESCs. C-peptide was also observed to increase matrix metallopeptidase-9 (MMP9) activity by increasing MMP9 expression and decreasing the expression of metallopeptidase inhibitor 1 (TIMP1) and TIMP3. Their expression was modulated by the direct binding of β-catenin in the regulatory region of the promoter of MMP9, TIMP1, and TIMP3. Inhibition of either β-catenin or MMP9 dampened C-peptide-enhanced migration in UnD-ESCs. Together, these findings suggest that C-peptide levels are critical for the regulation of UnD-ESC migration, providing evidence for the association between C-peptide levels and the failure rate of trophoblast invasion by inducing abnormal migration in UnD-ESCs in hyperinsulinemia or PCOS patients.

Highlights

  • The motility and invasion of endometrial stromal cells (ESCs) are essential for successful decidualization and human embryonic trophoblast invasion (Weimar et al, 2013; Vinketova et al, 2016), leading to the occurrence and maintenance of pregnancy (Gellersen et al, 2010)

  • These results suggest that C-peptide has a profound positive effect on the migration of UnD-ESCs and JEG-3 cells

  • We found that the putative binding site of TCF-1 was present in the proximal promoter regions of matrix metallopeptidase-9 (MMP9), the expression of metallopeptidase inhibitor 1 (TIMP1), and TIMP3, which are important for cellular movement through the extracellular matrix (ECM) (Supplementary Figure S4)

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Summary

Introduction

The motility and invasion of endometrial stromal cells (ESCs) are essential for successful decidualization and human embryonic trophoblast invasion (Weimar et al, 2013; Vinketova et al, 2016), leading to the occurrence and maintenance of pregnancy (Gellersen et al, 2010). Decidualization is the differentiation of endometrial stromal cells (ESCs) in response to progesterone during the menstrual cycle and embryo implantation (Zhu et al, 2014). The invasive and migratory capacities of ESCs are essential for endometrial tissue remodeling during decidualization and implantation (Weimar et al, 2013), supported by the fact that decidualized ESCs exhibit greater invasive activity than undecidualized ESCs (UnD-ESCs) (Gellersen et al, 2010). Successful implantation is associated with the wellregulated migration of D-ESCs, subsequent secretion of matrix metalloproteinases (MMPs) from D-ESCs, and the abundance of extra villous trophoblast cells (Grewal et al, 2008; Weimar et al, 2013; Macklon and Brosens, 2014). Tissue inhibitors of MMPs (TIMP, metallopeptidase inhibitor), a key regulator of MMP9 activity, play a key role in maintaining the homeostasis of endometrial migration and early implantation by altering trophoblast invasion (Fluhr et al, 2008)

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