Epithelial-To-Mesenchymal Transition and Migration of Human Peritoneal Mesothelial Cells Undergoing Senescence

Abstract

Background Epithelial-to-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs) contributes to fibrotic thickening of the peritoneum that develops in patients on peritoneal dialysis (PD). The process is thought to be largely mediated by transforming growth factor-beta (TGF-β). As TGF-β has also been implicated in senescence of HPMCs, we have performed an exploratory study to examine if senescent HPMCs can undergo EMT. Methods Omentum-derived HPMCs were rendered senescent by repeated passages in culture. Features of EMT were assessed by immunostaining and quantitative polymerase chain reaction (qPCR) at various stages of the HPMC lifespan and after treatment with or without TGF-β. The motility of HPMCs was assessed in a scratch wound migration assay. Results Replicative senescence of HPMCs was associated with a gradual increase in the constitutive expression of EMT markers, including increased production of extracellular matrix proteins. However, senescent HPMCs also retained epithelial cell features such as cytokeratin, calretinin, and E-cadherin and showed decreased, rather than increased, motility. In contrast, exposure to TGF-β resulted in an up-regulation of mesenchymal markers and down-regulation of epithelial markers. Such effects of TGF-β occurred both in young and senescent cells, although they were less pronounced in senescence. Conclusions Senescence of HPMCs is associated with spontaneous development of several EMT features. At the same time, senescent HPMCs preserve epithelial cell-like characteristics and are less prone to develop a full EMT phenotype in response to TGF-β. These observations may support the concept of cellular senescence being antagonistically pleiotropic with regard to EMT.

Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer

“…Moreover, we previously reported compression-induced changes in OvCa multicellular aggregates correlated with upregulation of epithelial-mesenchymal transition (EMT)-associated genes 11 . Together these data suggest that ascites-induced compression may play a role in mesothelial-mesenchymal transition 21 , 44 . A limitation of the current study is the lack of information regarding the uniformity of ascites-induced compression throughout structures of the peritoneal cavity impacted by OvCa metastases.…”

“…During OvCa progression, peritoneal MC undergo morphological and molecular modifications that contribute to disease progression 21 . As the MC monolayer lines the inner surface of the peritoneum and covers peritoneal organs, these cells are directly subjected to ascites-induced compression.…”

Proteomic profile of mesothelial exosomes isolated from peritoneal dialysis effluent of children with focal segmental glomerulosclerosis

“…Out of the 2490 identified proteins, 10% (251) were FSGS-associated and 40% (995) were involved in fibrosis. Most of them were included in the transforming growth factor β (TGFβ) signalling pathway, playing a major role in EMT onset 16 , 38 , 39 . Additionally, the WGCNA algorithm identified a group of mesothelial exosome proteins that maximized the discrimination between FSGS and No FSGS and were highly correlated to peritoneal dialysis vintage, fibrosis, EMT and PM disease.…”

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis

“…Furthermore, an intriguing feature of senescent HPMCs was described. In those cells, both markers typical for mesenchymal and epithelial phenotype were observed, which usually indicates a partial MMT process [ 119 ]. Thus, there is a possible phenotypical connection between senescence and MMT and inflammatory factors that can induce either of the processes.…”