Endometrial epithelial–mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia

Kazuya Kusama, Yuta Fukushima, Y Fukushima, Kanoko Yoshida, K Yoshida, H Sakakibara, Hideya Sakakibara, Naoya Tsubata, N Tsubata, M Yoshie, Mikihiro Yoshie, Junya Kojima, J Kojima, Hirotaka Nishi, H Nishi, Kazuhiro Tamura
Molecular human reproduction · 2021 · vol. 27(6) · doi:10.1093/molehr/gaab036 · PMID:33983443 · W3160073662
article OA: bronze CC0 ⤵ 14 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

Hypoxia and menstruation-related inflammatory factors like PGE2 and thrombin induce epithelial-mesenchymal transition and cell migration in endometrial cells, exacerbated by CXCL12 secreted from stromal cells.

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Abstract

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal haemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or oestrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Cell Hypoxia Endometriosis Endometrium Epithelial-Mesenchymal Transition Menstruation Menstruation Disturbances Adult Biomarkers Cell Culture Techniques, Three Dimensional Cell Movement Cell Movement Cells, Cultured Chemokine CXCL12 Chemokine CXCL12 Chemokine CXCL12 Dinoprostone Dinoprostone Endometriosis Endometriosis Endometrium

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References (45)

Cited by (14)

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