Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-β Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis

Aseem, Sayed Obaidullah; Jalan‐Sakrikar, Nidhi; Chi, Cheng; Navarro‐Corcuera, Amaia; Assuncao, Thiago M. de; Hamdan, Feda H.; Chowdhury, Shiraj A.; Johnsen, Steven A.; Shah, Vijay H.; Huebert, Robert C.

doi:10.1053/j.gastro.2020.10.008

Cited by 28 publications

(16 citation statements)

References 36 publications

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“…Many studies have linked oxidative stress to liver fibrosis. It has been discovered that ROS can activate KCs (Kupffer cells) to trigger the inflammatory response, which subsequently leads to HSC (activated hepatic stellate cells) activation to create ECM proteins [ 29 , 30 ] and fibrosis. It will offer a fresh look at the treatment strategy for BA's fibrosis mechanism.…”

Section: Discussionmentioning

confidence: 99%

The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia

Zhang

2022

Computational and Mathematical Methods in Medicine

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Background. Biliary atresia (BA) is an uncommon illness that causes the bile ducts outside and within the liver to become clogged in babies. If left untreated, the cholestasis causes increasing conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. BA has a complicated aetiology, and the mechanisms that drive its development are unknown. The objective of this study was to show the role of probable critical genes involved in the pathophysiology of biliary atresia. Methods. We utilised the public Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE46960 to find differentially expressed genes (DEGs) in 64 biliary atresia newborns, 14 infants with various causes of intrahepatic cholestasis, and 7 deceased-donor children as control subjects in our study. The relevant information was looked into. The important modules were identified after functional enrichment, GO and KEGG pathway analyses, protein-protein interaction (PPI) network analyses, and GSEA analysis. Results. The differential expression analysis revealed a total of 22 elevated genes. To further understand the biological activities of the DEGs, we run functional enrichment analyses on them. Meanwhile, KEGG analysis has revealed significant enrichment of pathways involved in activating cross-talking with inflammation and fibrosis in BA. SERPINE1, THBS1, CCL2, MMP7, CXCL8, EPCAM, VCAN, ITGA2, AREG, and HAS2, which may play a significant regulatory role in the pathogenesis of BA, were identified by PPI studies. Conclusion. Our findings suggested 10 hub genes and probable mechanisms of BA in the current study through bioinformatic analysis.

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Section: Discussionmentioning

confidence: 99%

The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia

Zhang

2022

Computational and Mathematical Methods in Medicine

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“…Synovial fibrosis in OA is associated with joint pain and stiffness, with the expression of TGF-β considered the most critical cytokine. TGF-β signaling is pivotal in fibrogenesis and thus TGF-β1 is widely used to model fibrosis in vitro [ 29 – 32 ]. In the present study, we explored whether TGF-β1 influences the proliferation of FLS and found that a concentration of 2.5 ng/ml TGF-β1 promoted the greatest FLS proliferation.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

et al. 2021

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Background Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-fibrotic drug with additional anti-inflammatory properties. However, the influence of PFD on OA is unknown. Methods Proliferation of human fibroblast-like synoviocytes (FLSs) after treatment with TGF-β1 or PFD was evaluated using a Cell Counting Kit-8 assay and their migration using a Transwell assay. The expression of fibrosis-related genes (COL1A1, TIMP-1, and ACTA-2) and those related to inflammation (IL-6 and TNF-α) was quantified by real-time quantitative PCR. The protein expression levels of COL1A1, α-SMA (coded by ACTA-2), IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay. A rabbit model of OA was established and then PFD was administered by gavage. The expression of genes related to fibrosis (COL1A1, TIMP-1, and ADAM-12) and inflammation (IL-6 and TNF-α) was measured using RNA extracted from the synovium. Synovial tissue was examined histologically after staining with H&E, Masson’s trichrome, and immunofluorescence. Synovitis scores, the volume fraction of collagen, and mean fluorescence intensity were calculated. Degeneration of articular cartilage was analyzed using a Safranin O-fast green stain and OARSI grading. Results The proliferation of FLSs was greatest when induced with 2.5 ng/ml TGF-β1 although it did not promote their migration. Therefore, 2.5 ng/ml TGF-β1 was used to stimulate the FLSs and evaluate the effects of PFD, which inhibited the migration of FLSs at concentrations as low as 1.0 mg/ml. PFD decreased the expression of COL1A1 while TGF-β1 increased both mRNA and protein expression levels of IL-6 but had no effect on α-SMA or TNF-α expression. PFD decreased mRNA expression levels of COL1A1, IL-6, and TNF-α in vivo. H&E staining and synovitis scores indicated that PFD reduced synovial inflammation, while Masson’s trichrome and immunofluorescence staining suggested that PFD decreased synovial fibrosis. Safranin O-Fast Green staining and the OARSI scores demonstrated that PFD delayed the progression of OA. Conclusions PFD attenuated synovial fibrosis and inflammation, and postponed the progression of osteoarthritis in a modified Hulth model of OA in rabbits, which was related to its anti-fibrotic and anti-inflammatory properties.

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“…Predictably, the CM from these highly secretory cholangiocytes has the ability to more potently activate HSCs through paracrine mechanisms of epithelial-mesenchymal crosstalk, consistent with previous observations of the cholangiocyte secretome activating HSCs. (15,21) Our study, while intriguing, has a variety of important limitations to be considered. First, while we have recruited a large number of subjects for skin biopsy, the time-and resource-intensive nature of the iPSC and organoid technologies leads to smaller numbers ultimately being analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…Predictably, the CM from these highly secretory cholangiocytes has the ability to more potently activate HSCs through paracrine mechanisms of epithelial–mesenchymal crosstalk, consistent with previous observations of the cholangiocyte secretome activating HSCs. ( 15,21 )…”

Section: Discussionmentioning

confidence: 99%

Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation

et al. 2021

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Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient-specific, in vitro models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three-dimensional matrigel-based culture to induce formation of cholangioids. RNA sequencing (RNA-seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA-seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three-dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC-derived cholangioids. Congruent with this, PSC-derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin-6, and chemokine (C-C motif ) ligand 2. Conditioned media (CM) from PSC-derived iDCs more potently activated hepatic stellate cells compared to control CM. Conclusion: We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease-specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids. (Hepatology Communications 2021;0:1-16).

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Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-β Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis

Cited by 28 publications

References 36 publications

The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia

The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation

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