Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135462 | GEO | 2022/07/01
REPOSITORIES: GEO
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Project description:Dynamic analysis of m6A methylation spectroscopy during progression and reversal of hepatic fibrosis
| PRJNA558972 | ENA
Project description:We developed in vivo reprogramming of myofibroblasts (MFs) into induced hepatocytes (MF-iHeps) using adeno-associated virus serotype 6 (AAV6) vectors expressing hepatic transcription factors in MF fate tracing (Lrat-Cre;R26R-ZsGreen) mice with carbon tetrachloride (CCl4)-induced liver fibrosis. To determine whether MF-iHeps acquire full hepatocyte differentiation, we used microarrays to profile their global gene expression. We isolated MF-iHeps and primary hepatocytes (Heps) from the same mice by laser-capture microdissection (5 and 3 biological replicates, respectively) and hepatic MFs from CCl4-treated littermates isolated by fluorescence-activated cell sorting (3 biological replicates). Total RNA was extracted, transcribed, amplified and biotin labeled. Labeled cDNA targets were hybridized to GeneChip Mouse Gene 1.0 ST arrays (Affymetrix).
2016-05-17 | E-GEOD-81491 | biostudies-arrayexpress
Project description:We developed in vivo reprogramming of myofibroblasts (MFs) into induced hepatocytes (MF-iHeps) using adeno-associated virus serotype 6 (AAV6) vectors expressing hepatic transcription factors in MF fate tracing (Lrat-Cre;R26R-ZsGreen) mice with carbon tetrachloride (CCl4)-induced liver fibrosis. To determine whether MF-iHeps acquire full hepatocyte differentiation, we used microarrays to profile their global gene expression.
2016-05-17 | GSE81491 | GEO
Project description:Liver fibrosis resulting from chronic liver damage constitutes a major health care bur-den worldwide; however, no antifibrogenic agents are currently available. Our previ-ous study reported that the small molecule NPLC0393 extracted from the herb Gyno-stemma pentaphyllum exerts efficient antifibrotic effects both in vivo and in vitro. In this study, a TMT-based quantitative proteomic study using a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was performed to identify the potential target of NPLC0393. Combining this study with protein-protein interaction network analysis of differentially expressed proteins between the CCl4 model and NPLC0393 treatment groups, we focused on the function of NDRG2 involved in cell differentia-tion. In vitro studies showed that NPLC0393 prevented the TGF-β1 stimula-tion-induced decrease in the NDRG2 level in hepatic stellate cells (HSCs). Functional studies indicated that NDRG2 can inhibit the activation of HSCs by preventing the phosphorylation of ERK and JNK. Furthermore, knockdown of NDRG2 abolished the ability of NPLC0393 to inhibit HSC activation. In conclusion, these results pro-vide information on the mechanism underlying the antifibrotic effect of NPLC0393 and shed new light on the potential therapeutic function of the TGF-β1/NDRG2/MAPK signaling axis in liver fibrosis.
2021-09-09 | PXD019448 | Pride
Project description:Long noncoding RNAs (lncRNAs) play important roles in various biological processes; however, few have been identified that regulate hepatic stellate cells (HSCs) activation and the progression of liver fibrosis. To identify the possible roles of lncRNAs in regulating liver fiboris and the potential of lncRNAs as molecular markers for liver fiboris, we systematically analyzed the regulation of lncRNAs and mRNAs in a mouse model of carbon tetrachloride (CCl4)-induced liver fibrogenesis by microarray analysis, which revealed a panel of lncRNAs and mRNAs that were specifically regulated in livers of mice undergoing hepatic fibrosis. To identify the possible roles of lncRNAs in regulating liver fiboris and the potential of lncRNAs as molecular markers for liver fiboris,we determined the lncRNA and mRNA expression profiles in the livers of fibrotic mice and normal mice by lncRNA and mRNA microarrays.
2016-04-25 | GSE80601 | GEO
Project description:Hepatic stellate cells (HSCs) experience phenotypic transformation, from the quiescent phenotype to the activated one, after different etiologies of liver injury. Liver fibrosis is then occurred upon the activation of HSCs. miR-16 deficiency is identified to be an important characteristic of HSCs activation. We used Affymetrix rat 230 2.0 arrays (Affymetrix, Santa Clara, U.S.A.) to uncover the global alternations of transcriptome under miR-16 restoration. We isolated quiescent hepatic stellate cells (HSCs) from adult male SD rats (normal control group) by in situ perfusion and density-gradient centrifugation. Activated HSCs were separated from rats of fibrosis model group, which were treated by 40% carbon tetrachloride (CCl4) for 8 weeks, by means of liver section, digestion and sequential centrifugation. Quiescent and activated HSCs were then divided into 4 groups at random, namely quiescent HSCs, activated HSCs, pLV-miR-16-treated HSCs and pLV-GFP-treated HSCs. The pLV-miR-16-treated group, pLV-GFP-treated group were infected with pLV-miR-16 and pLV-GFP, respectively.
2012-08-28 | E-GEOD-40381 | biostudies-arrayexpress
Project description:Background & Aims Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of hepatic stellate cells (HSCs) and hepatic fibrosis was examined. Approach & Results PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin (α-SMA) in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl4, MCD, or western diet plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin-immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with Mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of transforming growth factor β (TGFβ) in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl4-treated mice. Conclusions In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs via Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
2023-03-29 | GSE227902 | GEO
Project description:Background & Aims Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of hepatic stellate cells (HSCs) and hepatic fibrosis was examined. Approach & Results PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin (α-SMA) in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl4, MCD, or western diet plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin-immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with Mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of transforming growth factor β (TGFβ) in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl4-treated mice. Conclusions In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs via Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
2023-03-29 | GSE227901 | GEO
Project description:Wnt/β-catenin is involved in every aspect of embryonic development and in the pathogenesis of many human diseases, and is also implicated in organ fibrosis. However, the role of β-catenin-mediated signaling on liver fibrosis remains unclear. To explore this issue, the effects of PRI-724, a selective inhibitor of the cAMP-response element-binding protein-binding protein (CBP)/β-catenin interaction, on liver fibrosis were examined using carbon tetrachloride (CCl4)- or bile duct ligation (BDL)-induced mouse liver fibrosis models. Following repetitive CCl4 administrations, the nuclear translocation of β-catenin was observed only in the non-parenchymal cells in the liver. PRI-724 treatment reduced the fibrosis induced by CCl4 or BDL, accompanied by the suppression of S100A4 expression, a CBP/β-catenin transcript. C-82, an active form of PRI-724, inhibited the activation of isolated primary mouse quiescent hepatic stellate cells (HSCs) and promoted cell death in culture-activated HSCs. During the fibrosis resolution period, an increase in F4/80+ CD11b+ and Ly6Clow CD11b+ macrophages was induced by CCl4 and was sustained for two weeks thereafter, even after having stopped CCl4 treatment. PRI-724 accelerated the resolution of CCl4-induced liver fibrosis, and this was accompanied by increased matrix metalloproteinase (MMP)-9, MMP-2, and MMP-8 expression in intrahepatic leukocytes. These results suggest that the inhibition of CBP/β-catenin suppresses liver fibrosis through the inhibition of HSCs activation, the induction of activated HSC death, and the production of MMPs from macrophages. Thus, targeting the CBP/β-catenin interaction may become a new therapeutic strategy in treating liver fibrosis. We used microarrays to detail the global change of gene expression by PRI-724 (C-82)-treatment in culture-activated murine hepatic stellate cells.
2018-09-30 | GSE73603 | GEO
Project description:Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.
2016-09-21 | GSE45612 | GEO