MiR‐503 suppresses fibroblast activation and myofibroblast differentiation by targeting VEGFA and FGFR1 in silica‐induced pulmonary fibrosis

Wu, Qiuyun; Han, Lei; Gui, Wenwen; Wang, Feng; Yan, Wei; Jiang, Hua

doi:10.1111/jcmm.16051

Cited by 21 publications

(13 citation statements)

References 47 publications

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“…This is consistent with the role of FGFR1 in the stimulation of angiogenesis by mediating the proliferation of both endothelial and vascular smooth muscle cells [ 24 , 25 ]. The increased FGFR1 expression in the connective tissue cells has been previously explained by its upregulation mediated by TGF-β signaling, which leads to myofibroblast differentiation and increased extracellular matrix synthesis [ 45 , 46 ]. Myofibroblasts and TGF-β signaling seem to have a central role in the pathogenesis of DD [ 37 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Fibrosis-Associated Signaling Molecules Are Differentially Expressed in Palmar Connective Tissues of Patients with Carpal Tunnel Syndrome and Dupuytren’s Disease

et al. 2022

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Carpal tunnel syndrome (CTS) and Dupuytren’s disease (DD) are fibrotic conditions that affect the connective tissue of the hand and limit its functionality. The exact molecular mechanism underlying the fibrosis is unknown, and only some profibrotic factors have been investigated. In this cross-sectional study, we analyzed the expression of FGF signaling pathway molecules associated with fibrotic changes in the palmar fascia and the flexor retinaculum of 15 CTS patients and both clinically affected and unaffected palmar fascia of 15 DD patients, using immunofluorescence techniques. The expression of FGFR1, FGFR2, and CTGF in the blood vessel walls and surrounding connective tissue cells differed significantly between the analyzed groups, with changes in expression present even in clinically unremarkable tissues from DD patients. We also found altered expression of the analyzed factors, as well as TGF-β1 and syndecan-1 in DD-associated sweat glands, possibly implicating their role in the pathophysiology of the disease. The increased expression of profibrotic factors in the clinically unaffected palmar fascia of DD patients may indicate that more extensive excision is needed during surgical treatment, while the profibrotic factors could be potential targets for developing pharmacological therapeutic strategies against DD-associated fibrosis.

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Section: Discussionmentioning

confidence: 99%

Fibrosis-Associated Signaling Molecules Are Differentially Expressed in Palmar Connective Tissues of Patients with Carpal Tunnel Syndrome and Dupuytren’s Disease

et al. 2022

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“…Several studies demonstrated that miR-503 modulates myofibroblast transdifferentiation and fibrosis. Wu et al [ 26 ] demonstrated that miR-503 expression was decreased in TGF-β1 stimulated lung fibroblasts and upregulation of miR-503 attenuated CAF-like myofibroblastic phenotype in myofibroblasts. Several miRNAs are involved in cardiac fibrosis (reviewed in [ 27 ]), and another study has proposed that miR-503 modulates fibrosis by enhancing the ECM deposition in cardiac fibroblasts [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

et al. 2021

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Transforming growth factor-beta 1 (TGF-β1), a pro-fibrotic tumour-derived factor promotes fibroblast differentiation in the tumour microenvironment and is thought to contribute to the development of pro-tumourigenic cancer-associated fibroblasts (CAFs) by promoting myofibroblast differentiation. miRNA dysregulation has been demonstrated in myofibroblast transdifferentiation and CAF activation, however, their expression varies among cell types and with the method of fibroblast induction. Here, the expression profile of miRNA in human primary oral fibroblasts treated with TGF-β1, to derive a myofibroblastic, CAF-like phenotype, was determined compared to untreated fibroblasts. Myofibroblast transdifferentiation was determined by the expression of alpha-smooth muscle actin (α-SMA) and fibronectin-1 extra domain A (FN-EDA1) using quantitative real-time PCR (qRT-PCR) and western blot. The formation of stress fibres was assessed by fluorescence microscopy, and associated changes in contractility were assessed using collagen contraction assays. Extracellular vesicles (EVs) were purified by using size exclusion chromatography and ultracentrifugation and their size and concentration were determined by nanoparticle tracking analysis. miRNA expression profiling in oral fibroblasts treated with TGF-β1 and their extracellular vesicles was carried out using tiling low-density array cards. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform functional and pathway enrichment analysis of target genes. In this study, TGF-β1 induced a myofibroblastic phenotype in normal oral fibroblasts as assessed by expression of molecular markers, the formation of stress fibres and increased contractility. TaqMan Low-Density Array (TLDA) analysis demonstrated that miR-503 and miR-708 were significantly upregulated, while miR-1276 was significantly downregulated in TGF-β1-treated oral fibroblasts (henceforth termed experimentally-derived CAF, eCAF). The gene functional enrichment analysis showed that the candidate miRNAs have the potential to modulate various pathways; including the Ras associated protein 1 (Rap1), PI3K-Akt, and tumour necrosis factor (TNF) signalling pathways. In addition, altered levels of several miRNAs were detected in eCAF EV, including miR-142 and miR-222. No differences in size or abundance of EV were detected between eCAF and normal oral fibroblast (NOF). Little overlap was observed between changes in cellular and EV miRNA profiles, suggesting the possibility of selective loading of EV miRNA. The study reveals miRNA expression signature could be involved in myofibroblast transdifferentiation and the miRNA cargo of their EV, providing novel insight into the involvement of miRNA in CAF development and function.

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“…We can make informed assumptions and infer the involvement of specific cell types which do play an active role in tissue-specific co-expression networks ( 124 ). ATM is mainly found in endothelial and epithelial cells ( 125 , 126 ), FGFR1 in fibroblasts and epithelial cells ( 57 , 58 ), FBXW7 in hepatic stellate mesenchymal, mononuclear and pulmonary epithelial stem cells ( 60 – 62 ), ESR1 in myofibroblasts and epithelial cells ( 63 , 64 ), CCND1 in renal glomerular mesangial and hepatic stellate cells ( 66 , 127 ), HIF1A in renal epithelial cells and cardiac fibroblasts ( 68 , 128 ), CEBPB in hematopoietic and renal epithelial cells ( 70 , 71 ), NAMPT in hepatic stellate and renal glomerular mesangial cells ( 72 , 129 ), IRF1 in renal epithelial cells ( 76 ), SOCS1 in hepatocytes and macrophages ( 78 ), SOCS3 in cardiac fibroblasts ( 90 ), ICAM1 in endothelial cells ( 79 ), ETS1 in hepatic stellate and renal epithelial cells ( 130 , 131 ), IL7R in hepatic stellate cells ( 82 ), MMP1 in fibroblasts ( 83 , 132 ), HNF4A in hepatocytes ( 85 ), CCL2 in fibroblasts ( 86 , 133 ), CASP1 in hepatic endothelial cells ( 87 ) and STAT1 in macrophages ( 88 , 89 ). HSP90B1 , although it has been recently reported to be implicated in fibrosis ( 92 ), the specific cell type expressing it, still, remains undetermined.…”

Section: Discussionmentioning

confidence: 99%

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

Dovrolis

Filidou²,

Tarapatzi³

et al. 2022

Front. Immunol.

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IntroductionExtracellular matrix turnover, a ubiquitous dynamic biological process, can be diverted to fibrosis. The latter can affect the intestine as a serious complication of Inflammatory Bowel Diseases (IBD) and is resistant to current pharmacological interventions. It embosses the need for out-of-the-box approaches to identify and target molecular mechanisms of fibrosis.Methods and resultsIn this study, a novel mRNA sequencing dataset of 22 pairs of intestinal biopsies from the terminal ileum (TI) and the sigmoid of 7 patients with Crohn’s disease, 6 with ulcerative colitis and 9 control individuals (CI) served as a validation cohort of a core fibrotic transcriptomic signature (FIBSig), This signature, which was identified in publicly available data (839 samples from patients and healthy individuals) of 5 fibrotic disorders affecting different organs (GI tract, lung, skin, liver, kidney), encompasses 241 genes and the functional pathways which derive from their interactome. These genes were used in further bioinformatics co-expression analyses to elucidate the site-specific molecular background of intestinal fibrosis highlighting their involvement, particularly in the terminal ileum. We also confirmed different transcriptomic profiles of the sigmoid and terminal ileum in our validation cohort. Combining the results of these analyses we highlight 21 core hub genes within a larger single co-expression module, highly enriched in the terminal ileum of CD patients. Further pathway analysis revealed known and novel inflammation-regulated, fibrogenic pathways operating in the TI, such as IL-13 signaling and pyroptosis, respectively.DiscussionThese findings provide a rationale for the increased incidence of fibrosis at the terminal ileum of CD patients and highlight operating pathways in intestinal fibrosis for future evaluation with mechanistic and translational studies.

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MiR‐503 suppresses fibroblast activation and myofibroblast differentiation by targeting VEGFA and FGFR1 in silica‐induced pulmonary fibrosis

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 21 publications

References 47 publications

Fibrosis-Associated Signaling Molecules Are Differentially Expressed in Palmar Connective Tissues of Patients with Carpal Tunnel Syndrome and Dupuytren’s Disease

Fibrosis-Associated Signaling Molecules Are Differentially Expressed in Palmar Connective Tissues of Patients with Carpal Tunnel Syndrome and Dupuytren’s Disease

Myofibroblast transdifferentiation is associated with changes in cellular and extracellular vesicle miRNA abundance

Co-expression of fibrotic genes in inflammatory bowel disease; A localized event?

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