Mesothelial Cells Participate in Endometriosis Fibrogenesis Through Platelet-Induced Mesothelial-Mesenchymal Transition

Author:

Yan Dingmin1,Liu Xishi12,Xu Hong3,Guo Sun-Wei12ORCID

Affiliation:

1. Shanghai OB/GYN Hospital, Fudan University, Shanghai, China

2. Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China

3. Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

Abstract

Abstract Context While fibrosis in endometriosis has recently loomed prominently, the sources of myofibroblasts, the principal effector cell in fibrotic diseases, remain largely obscure. Mesothelial cells (MCs) can be converted into myofibroblasts through mesothelial-mesenchymal transition (MMT) in many fibrotic diseases and adhesion. Objective To evaluate whether MCs contribute to the progression and fibrogenesis in endometriosis through MMT. Setting, Design, Patients, Intervention, And Main Outcome Measures Dual immunofluorescence staining and immunohistochemistry using antibodies against calretinin, Wilms’ tumor-1 (WT-1), and α-smooth muscle actin (α-SMA) were performed on lesion samples from 30 patients each with ovarian endometrioma (OE) and deep endometriosis (DE), and 30 normal endometrial (NE) tissue samples. Human pleural and peritoneal MCs were co-cultured with activated platelets or control medium with and without neutralization of transforming growth factor β1 (TGF-β1) and/or platelet-derived growth factor receptor (PDGFR) and their morphology, proliferation, and expression levels of genes and proteins known to be involved in MMT were evaluated, along with their migratory and invasive propensity, contractility, and collagen production. Results The number of calretinin/WT-1 and α-SMA dual-positive fibroblasts in OE/DE lesions was significantly higher than NE samples. The extent of lesional fibrosis correlated positively with the lesional α-SMA staining levels. Human MCs co-cultured with activated platelets acquire a morphology suggestive of MMT, concomitant with increased proliferation, loss of calretinin expression, and marked increase in expression of mesenchymal markers. These changes coincided with functional differentiation as reflected by increased migratory and invasive capacity, contractility, and collagen production. Neutralization of TGF-β1 and PDGFR signaling abolished platelet-induced MMT in MCs. Conclusions MCs contribute to lesional progression and fibrosis through platelet-induced MMT.

Funder

National Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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