Telomere length profiles in primary human peritoneal mesothelial cells are consistent with senescence

Lopez-Anton, Melisa; Rudolf, A Hatz; Baird, Duncan Martin; Roger, Lauréline; Jones, Rhiannon E.; Witowski, Janusz; Fraser, Donald; Bowen, Timothy

doi:10.1016/j.mad.2017.03.010

Cited by 7 publications

(7 citation statements)

References 22 publications

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“…As previously described (25), replicative senescence of HPMCs was accompanied by a gradual loss of their uniform cobblestone appearance. Instead, senescent cells became greatly enlarged, irregular and vacuolated, and stained extensively for SA-β–Gal (Figure 1).…”

Section: Resultssupporting

confidence: 64%

“…It is believed that the potential of explanted cells to grow in culture depends on the proliferative history of cells, which is influenced both by the calendar age of the donor and by the previous environmental stresses. This complexity may be reflected by large heterogeneity in telomere length that can be seen in freshly isolated HPMCs (25).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…24 Peritoneal mesothelial cells have high sensitivity to the oxidative stress what translates into their accelerated senescence. 25 That may explain promotion of the mesothelial senescence treated with iron in our study.…”

Section: Discussionmentioning

confidence: 99%

Iron increases the profibrotic properties of the senescent peritoneal mesothelial cells

Bręborowicz

2023

Int J Artif Organs

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Background: Treatment of anemia in peritoneal dialysis patients often requires intravenous iron supplementation. Iron diffuses into the peritoneal cavity and is injurious to the peritoneum. We studied how intermittent exposure to iron changes the properties of the senescent peritoneal mesothelial cells (MC). Methods: Replicative senescence was induced in MC in control medium (Con) or in control medium with intermittent exposure to iron isomaltoside 15 µg/dL (Con-IIS). After 10 passages properties of MC from both groups were compared to MC not exposed to replicative senescence. Results: In senescent MC population doubling time was elongated, intracellular generation of free radicals and staining for β-galactosidase was stronger than in MC not exposed to replicative senescence. All these effects were stronger in MC intermittently exposed to IIS. In these cells intracellular iron content was also higher. Also expression of genes p21 and p53 was stronger in MC intermittently treated with IIS. In senescent cells higher release and expression of IL6 and TGFβ1 was observed and that effect was stronger in MC treated with iron. Senescent MC had reduced fibrinolytic activity, what may predispose to the peritoneal fibrosis. Synthesis of collagen was higher in senescent cells, more in MC treated with iron. Conclusion: MC aging results in change of their genotype and phenotype which lead to their profibrotic effect. Exposure to iron enhances these changes.

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“…We previously reported a significant cytoskeletal re-arrangement of HUVEC exposed to GDP-containing PD fluids, where major regulators of actin dynamics as well as of actin cytoskeletal structure were found to be disrupted [ 18 ]. Furthermore, cytoskeleton-associated proteins are involved in development of a senescent phenotype and alterations of junctions have both been described as effects of PD fluid exposure of mesothelial cells [ 21 , 26 , 37 , 38 ]. This common effect on one of the most important functions of peritoneal endothelial cells, the barrier function, could be directly linked to clinical PD technique failure, presented as loss of ultrafiltration or change of peritoneal transport rates and could be of high relevance regarding solutes transport during PD.…”

Section: Discussionmentioning

confidence: 99%

“…Other molecular pathways enriched by all PD fluids included acute phase response, integrin signaling, senescence, and fibrosis-related pathways. All of them—but especially fibrosis—are well-described pathomechanisms of the peritoneal membrane exposed to PD [ 7 , 37 , 38 , 39 , 40 , 41 ]. Different combinations of exogenous stressors (osmotic agent, pH, buffer system, toxic GDPs) which characterize the individual PD fluid properties also trigger more specific pathways.…”

Section: Discussionmentioning

confidence: 99%

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

Sacnun

Hoogenboom

Eibensteiner

et al. 2022

IJMS

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To replace kidney function, peritoneal dialysis (PD) utilizes hyperosmotic PD fluids with specific physico-chemical properties. Their composition induces progressive damage of the peritoneum, leading to vasculopathies, decline of membrane function, and PD technique failure. Clinically used PD fluids differ in their composition but still remain bioincompatible. We mapped the molecular pathomechanisms in human endothelial cells induced by the different characteristics of widely used PD fluids by proteomics. Of 7894 identified proteins, 3871 were regulated at least by 1 and 49 by all tested PD fluids. The latter subset was enriched for cell junction-associated proteins. The different PD fluids individually perturbed proteins commonly related to cell stress, survival, and immune function pathways. Modeling two major bioincompatibility factors of PD fluids, acidosis, and glucose degradation products (GDPs) revealed distinct effects on endothelial cell function and regulation of cellular stress responses. Proteins and pathways most strongly affected were members of the oxidative stress response. Addition of the antioxidant and cytoprotective additive, alanyl-glutamine (AlaGln), to PD fluids led to upregulation of thioredoxin reductase-1, an antioxidant protein, potentially explaining the cytoprotective effect of AlaGln. In conclusion, we mapped out the molecular response of endothelial cells to PD fluids, and provided new evidence for their specific pathomechanisms, crucial for improvement of PD therapies.

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Telomere length profiles in primary human peritoneal mesothelial cells are consistent with senescence

Cited by 7 publications

References 22 publications

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

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

Iron increases the profibrotic properties of the senescent peritoneal mesothelial cells

Proteome-Wide Differential Effects of Peritoneal Dialysis Fluid Properties in an In Vitro Human Endothelial Cell Model

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