Progesterone alters human cervical epithelial and stromal cell transition and migration: Implications in cervical remodeling during pregnancy and parturition.

Abstract

The cervix undergoes extensive remodeling throughout pregnancy and parturition. This process involves both ECM collagen degradation and cellular remodeling, which includes cell proliferation, transition and migration. Progesterone (P4) has been used clinically to delay cervical ripening and prevent preterm birth (PTB). However, the mechanisms by which progesterone affects cell transition and the migration of cervical epithelial and stromal cells are not yet fully known. In this study, we documented the role of a gestational level of P4 in the cellular transition (epithelial-mesenchymal transition [EMT] and mesenchymal-epithelial transition [MET]), cell migration, and inflammatory responses of endocervical epithelial cells (EEC) and cervical stromal cells (CSC). EEC and CSC were treated with LPS and P4 for 6 days. The epithelial:mesenchymal ratio (regular microscopy and cell shape index analysis), shift in intermediate filaments (immunofluorescence microscopy and western blot analyses for cytokeratin [CK]-18 and vimentin), adhesion molecules and transcription factors (western blot analyses for E-cadherin, N-cadherin and SNAIL), were used to determine growth characteristics and EMT and MET changes in EEC and CSC under the indicated conditions. To test cell remodeling, scratch assays followed by cellular analyses as mentioned above were performed. Inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor α [TNFα]) and matrix metallopeptidase 9 (MMP9) were measured by ELISA. LPS promoted EMT (decreased cell shape index, decreased CK-18 and E-cadherin, increased vimentin, N-cadherin, and SNAIL), and increased IL-6 and MMP9 production by EEC. A gestational level of P4 prevented LPS-induced EMT in EEC and exhibited anti-inflammatory effect in both EEC and CSC. LPS slowed down wound healing in CSC but P4 treatment prevented the negative impact of LPS in CSC wound healing. These results may explain the cellular mechanisms by which P4 helps to stabilize the cervical epithelial barrier and preserve the mechanical and tensile strength of the cervical stromal layer, which are important in normal cervical remodeling processes during pregnancy.

• Authors: Ourlad Alzeus G Tantengco, Lauren S Richardson, Joy Vink, Talar Kechichian, Paul Mark B Medina, Richard B Pyles, Ramkumar Menon
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 529 Pg. 111276 (06 01 2021) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 33823217 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Antigens, CD
• CDH1 protein, human
• CDH2 protein, human
• Cadherins
• IL6 protein, human
• Interleukin-6
• Keratin-18
• Lipopolysaccharides
• SNAI1 protein, human
• Snail Family Transcription Factors
• VIM protein, human
• Vimentin
• Progesterone
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Antigens, CD (genetics, metabolism)
• Cadherins (genetics, metabolism)
• Cell Line, Transformed
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cervix Uteri (cytology, drug effects, metabolism)
• Epithelial Cells (cytology, drug effects, metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Interleukin-6 (genetics, metabolism)
• Keratin-18 (genetics, metabolism)
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Parturition
• Pregnancy
• Premature Birth (genetics, metabolism, pathology)
• Progesterone (metabolism, pharmacology)
• Signal Transduction
• Snail Family Transcription Factors (genetics, metabolism)
• Stromal Cells (cytology, drug effects, metabolism)
• Vimentin (genetics, metabolism)