MiRNA profiling in primary human peritoneal mesothelial cells (HPMCs) and TGF-β1-stimulated
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79006 | GEO | 2017/04/05
SECONDARY ACCESSION(S): PRJNA381562
REPOSITORIES: GEO
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Project description:Peritoneal fibrosis is a major complication of long-term peritoneal dialysis (PD), leading to ultrafiltration failure and sometimes life threatening encapsulating peritoneal sclerosis. Fibrosis is driven by activated myofibroblasts that are derived, in part, from mesothelial-to-mesenchymal transition (MMT). We aimed to discover novel mediators of MMT and then experimentally exploit them to prevent peritoneal fibrosis. Using an antibody to HBME-1 and streptavidin nanobead technology, we first pioneered a novel method to purify rat mesothelial cells. After exposing mesothelial cells to transforming growth factor β1 (TGFβ1), we undertook RNAseq whole transcriptome analyses and outlined, the expression profile of sorted mesothelial cells at pre- and post- MMT.
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Project description:Despite their emerging relevance to fully understand disease pathogenesis, we have as yet a poor understanding as to how biomechanical signals are integrated with specific biochemical pathways to determine cell behaviour. Mesothelial-to-mesenchymal transition (MMT) markers colocalized with TGF-beta1-dependent signalling and yes-associated protein (YAP) activation across biopsies from different pathologies exhibiting peritoneal fibrosis, supporting mechanotransduction as a central driving component of these class of fibrotic lesions and its crosstalk with specific signaling pathways. Transcriptome and proteome profiling of the response of mesothelial cells (MCs) to linear cyclic stretch revealed molecular changes compatible with bona fide MMT, which (i) overlapped with established YAP target gene subsets, and (ii) were largely dependent on endogenous TGF-beta1 signaling. Importantly, TGF-beta1 blockade blunts the transcriptional upregulation of the se gene signatures, but not the mechanical activation and nuclear translocation of YAP per se. We studied the role therein of caveolin-1 (Cav1), a plasma membrane mechanotransducer. Exposure of Cav1-deficient MCs to cyclic stretch led to a robust upregulation of MMT-related gene programs, which was blunted upon TGF-beta1 inhibition. Conversely, Cav1 depletion enhanced both TGF-beta1 and TGFBRI expression. Cav1 genetic deficiency exacerbated MMT and PA fibrosis in an experimental model of peritoneal ischaemic buttons. Taken together, these results support that Cav1-YAP/TAZ fine-tune the fibrotic response through the modulation of MMT, onto which TGF-beta1-dependent signaling coordinately converges. Our findings reveal a cooperation between biomechanical and biochemical signals in the triggering of MMT, representing a novel potential opportunity to intervene mechanically-induced disorders coursing with peritoneal fibrosis, such as post-surgical adhesions. This SuperSeries is composed of the SubSeries listed below.
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Project description:Peritoneal dialysis (PD) is an effective form of renal replacement therapy. A significant proportion of patients who initiate PD suffer from PD-related clinical complications, including peritoneal membrane damage, which may limit the duration of treatment. Mesothelial-to-mesenchymal transition (MMT) significantly contributes to the peritoneal dysfunction related to PD. Hence, we analyzed the genetic reprograming of the MMT-process with the aim to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping of MMT induced in vitro and MMT of effluent-derived mesothelial cells (ex vivo), and that MMT, both in vitro and ex vivo, is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. According to cellular morphology and the number of altered genes and pathways, the MMT ex vivo could be subdivided into two stages: early/epitheliod and advanced/non-epitheliod. We could demonstrate by RT-PCR array analysis that a number of genes differentially expressed in effluent-derived non-epitheliod cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Among the secreted proteins that are up-regulated along the MMT process thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were selected to be measured in PD effluents. TSP1, COL13 and VEGFA, but not GREM1, showed significant differences between early and advanced stages of MMT, and their expression were associated with high peritoneal transport status. The results establish a proof of concept about the feasibility of MMT-associated secreted proteins as biomarkers in PD.
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Project description:Peritoneal dialysis (PD) is an effective form of renal replacement therapy. A significant proportion of patients who initiate PD suffer from PD-related clinical complications, including peritoneal membrane damage, which may limit the duration of treatment. Mesothelial-to-mesenchymal transition (MMT) significantly contributes to the peritoneal dysfunction related to PD. Hence, we analyzed the genetic reprograming of the MMT-process with the aim to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping of MMT induced in vitro and MMT of effluent-derived mesothelial cells (ex vivo), and that MMT, both in vitro and ex vivo, is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. According to cellular morphology and the number of altered genes and pathways, the MMT ex vivo could be subdivided into two stages: early/epitheliod and advanced/non-epitheliod. We could demonstrate by RT-PCR array analysis that a number of genes differentially expressed in effluent-derived non-epitheliod cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Among the secreted proteins that are up-regulated along the MMT process thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were selected to be measured in PD effluents. TSP1, COL13 and VEGFA, but not GREM1, showed significant differences between early and advanced stages of MMT, and their expression were associated with high peritoneal transport status. The results establish a proof of concept about the feasibility of MMT-associated secreted proteins as biomarkers in PD.
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Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.
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