Endometriotic mesenchymal stem cells promote the fibrosis process of endometriosis through paracrine TGF‐β1 mediated RASAL1 inhibition

Ying Feng, Dong Han, Han Dong, Buzhen Tan
Journal of Obstetrics and Gynaecology Research · 2023 · vol. 50(3) , pp. 467–477 · doi:10.1111/jog.15851 · PMID:38113862 · W4389938479
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Abstract

BACKGROUND: Endometrial-derived stem cells are key players in endometriosis (EMs) pathogenesis, while the mechanism involved is still unclear. Herein, the role and regulatory mechanism of endometriotic mesenchymal stem cells (ecto-MSCs) in regulating fibrosis during EMs progression were investigated. METHODS: The mRNA and protein expressions were assessed using qRT-PCR, western blot, and immunofluorescence. Flow cytometry was adopted to analyze the markers of MSCs. Transwell assay was adopted to examine endometriotic stromal cells (ESCs) migration and invasion. The interactions between DNMT3A and RASAL1 were analyzed by ChIP assay. In addition, MSP was employed to detect RASAL1 promoter methylation level. RESULTS: Ecto-MSCs promoted ESCs migration, invasion, and fibrosis process by TGF-β1 paracrine. It was subsequently revealed that TGF-β1 upregulated DNMT3A in ESCs in a SMAD3-dependent manner. As expected, DNMT3A knockdown abolished ecto-MSCs' facilitation on ESCs migration, invasion, and fibrosis process. DNMT3A, as a methyltransferase, reduced RASAL1 expression in TGF-β1-treated ESCs by increasing RASAL1 promoter methylation level. RASAL1, as an antifibrotic protein, was lowly expressed in TGF-β1-treated ESCs, and its overexpression ameliorated TGF-β1-induced increase in ESCs migration, invasion, and fibrosis process. CONCLUSION: TGF-β1 secreted by ecto-MSCs facilitated fibrogenesis in EMs through SMAD3/DNMT3A-mediated RASAL1 inhibition.

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endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Mesenchymal Stem Cells Mesenchymal Stem Cells Mesenchymal Stem Cells Mesenchymal Stem Cells Mesenchymal Stem Cells Mesenchymal Stem Cells

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