Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
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PROVIDER: PRJNA973076 | ENA |
REPOSITORIES: ENA
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Project description:The LX2 cells were subjected to TGFβ (5ng/ml) stimulus with or without STING inhibitor IFM-004490-7 10μM (STINGX) pretreatment. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different groups (Control, TGFβ, STINGX+TGFβ)
2023-05-16 | GSE232640 | GEO
Project description:Hepatocellular carcinoma (HCC) emerges from chronic inflammation to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that while p62 positively regulates STING ubiquitination by TRIM32 by displacing NBR1, which results in the activation of the interferon (IFN) cascade, NBR1 prevents TRIM32 interaction with and the activation of STING, leading to impaired IFN synthesis. NBR1 also antagonizes STING function by promoting its trafficking from the Golgi to the endosome-lysosomal degradative cascade independent of autophagy. Importantly, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs. The upregulation of the STING-IFN pathway by NBR1 deficiency enhances the anti-tumor response mediated by CD8+ T cells. These results identify NBR1 as a synthetic vulnerability of p62-deficiency in HSCs. NBR1 loss, by promoting the STING/IFN pathway, boosts anti-tumor CD8+ T cell responses to restrain HCC.
2024-10-22 | GSE254277 | GEO
Project description:Hepatocellular carcinoma (HCC) emerges from chronic inflammation to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that while p62 positively regulates STING ubiquitination by TRIM32 by displacing NBR1, which results in the activation of the interferon (IFN) cascade, NBR1 prevents TRIM32 interaction with and the activation of STING, leading to impaired IFN synthesis. NBR1 also antagonizes STING function by promoting its trafficking from the Golgi to the endosome-lysosomal degradative cascade independent of autophagy. Importantly, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs. The upregulation of the STING-IFN pathway by NBR1 deficiency enhances the anti-tumor response mediated by CD8+ T cells. These results identify NBR1 as a synthetic vulnerability of p62-deficiency in HSCs. NBR1 loss, by promoting the STING/IFN pathway, boosts anti-tumor CD8+ T cell responses to restrain HCC.
2024-10-22 | GSE254276 | GEO
Project description:Gene expression of mouse hepatic stellate cells was characterized under the following conditions: Quiescent (isolated from normal mouse liver) and reverted (isolated from mouse liver treated with 4 injections of carbontetrachloride followed by 45 day rest period) Affymetrix Mouse 1.0ST gene expression measurements were used to characterize the transcriptomic basis in quiescent hepatic stellate cells, isolated from normal liver, and reverted hepatic stellate cells, isolated from liver treated with 4 injections of CCl4 followed by a 45 day rest period. Gene expression of mouse hepatic stellate cells was characterized under the following conditions: A. Quiescent control hepatic stellate cells (n=4). B. Reverted hepatic stellate cells (n=4).
2014-05-05 | E-GEOD-38648 | biostudies-arrayexpress
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
Project description:Analysis of hepatic stellate cells isoltaed from wild-type, TLR4-/-, and CD44-/- mice. TLR4 and CD44 are major hyaluronic acid receptors. Results provide insight into the effects of TLR4 and CD44 loss in hepatic stellate cells.
2020-01-01 | GSE109200 | GEO
Project description:Early during culture of primary mouse HSCs gene expression changes. These expression alterations can be affected by treating cells with histone deacetylase inhibitor, valproic acid Primary mouse Hepatic stellate cells were cultured for short periods of time (4-16-64h) in presence or absence of valproic acid. Gene expression analysis (mouse Gene 1.0 ST arrays according to manufacturerM-bM-^@M-^Ys manual 701880Rev4 (Affymetrix, Santa Clara, CA)), in vitro stellate cell activation and inhibition of the activation by valproic acid treatment.
2014-01-01 | E-GEOD-51882 | biostudies-arrayexpress
Project description:Hepatic Stellate Cell Activation after 72hr
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Project description:To investigate the role of Tet2 deficient immune cells in hepatic stellate cell activation, wild type or Tet2 deficient B cells, T cells, and hepatic macrophages were isolated and co-cultured with purified hepatic stellate cells. Gene expression profiling analysis of bulk hepatic stellate cell RNA was then performed.
2023-02-07 | GSE223693 | GEO
Project description:The molecular determinants of a healthy human liver cell phenotype remain largely uncharacterized. In addition, the gene expression changes associated with activation of primary human hepatic stellate cells, a key event during fibrogenesis, remain poorly characterized. Here, we provide the transriptomic profile underpinning the healthy phenotype of human hepatocytes, liver sinusoidal endothelial cells (LSECs) and quiescent hepatic stellate cells (qHSCs) as well as activated HSCs (aHSCs) We assess the transcriptome for purified, non-cultured human hepatocytes, liver sinusoidal cells (LSECs) and quiescent hepatic stellate cells (qHSCs) as well as culture-activated HSCs (aHSCs). Hepatocytes (n=2 donors), LSECs (n=3), qHSCs (n=3) and in vitro activated HSCs (n=3; from the same donors as the qHSCs and LSECs) were used for this study.
2016-03-02 | E-GEOD-68000 | biostudies-arrayexpress