Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model
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BiBTeXTransforming growth factor (TGF)-β stimulates extracellular matrix (ECM) deposition during development of liver fibrosis and cirrhosis, the most important risk factor for the onset of hepatocellular carcinoma. In liver cancer, TGF-β is responsible for a more aggressive and invasive phenotype, orchestrating remodeling of the tumor microenvironment and triggering epithelial-mesenchymal transition of cancer cells. This is the scientific rationale for targeting the TGF-β pathway via a small molecule, galunisertib (intracellular inhibitor of ALK5) in clinical trials to treat liver cancer patients at an advanced disease stage. In this study, the hypothesis that galunisertib modifies the tissue microenvironment via inhibition of the TGF-β pathway is tested in an experimental preclinical model. At the age of 6 months, Abcb4ko mice-a well-established model for chronic liver disease development and progression-are treated twice daily with galunisertib (150 mg/kg) via oral gavage for 14 consecutive days. Two days after the last treatment, blood plasma and livers are harvested for further assessment, including fibrosis scoring and ECM components. The reduction of Smad2 phosphorylation in both parenchymal and non-parenchymal liver cells following galunisertib administration confirms the treatment effectiveness. Damage-related galunisertib does not change cell proliferation, macrophage numbers and leucocyte recruitment. Furthermore, no clear impact on the amount of fibrosis is evident, as documented by PicroSirius red and Gomori-trichome scoring. On the other hand, several fibrogenic genes, e.g., collagens (Col1α1 and Col1α2), Tgf-β1 and Timp1, mRNA levels are significantly downregulated by galunisertib administration when compared to controls. Most interestingly, ECM/stromal components, fibronectin and laminin-332, as well as the carcinogenic β-catenin pathway, are remarkably reduced by galunisertib-treated Abcb5ko mice. In conclusion, TGF-β inhibition by galunisertib interferes, to some extent, with chronic liver progression, not by reducing the stage of liver fibrosis as measured by different scoring systems, but rather by modulating the biochemical composition of the deposited ECM, likely affecting the fate of non-parenchymal cells.
SEEK ID: https://seek.lisym.org/publications/97
DOI: 10.1007/s00204-018-2231-y
Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network
Publication type: Not specified
Journal: Arch Toxicol
Citation: Arch Toxicol 382(4) : 697
Date Published: 28th May 2018
Registered Mode: Not specified
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Created: 31st May 2018 at 12:31
Last updated: 8th Mar 2024 at 07:44
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Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM-Krebs Partnering, Forschungsnetzwerk LiSyM-Krebs, C-TIP-HCC network, SMART-NAFLD
Institutions: Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University
Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM PALs, LiSyM-Krebs Partnering, C-TIP-HCC network
Institutions: Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University
Liver Systems Medicine : striving to develop non-invasive methods for diagnosing and treating NAFLD by combining mathematical modeling and biological research. LiSyM, is a multidisciplinary research network, in which molecular and cell biologists, clinical researchers, pharmacologists and experts in mathematical modeling examine the liver in its entirety. LiSyM research focuses on the metabolic liver disease non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis ...
Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), LiSyM PALs, Project Management PTJ, LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)
Web page: https://www.lisym.org/
This comprises the whole LiSyM network
Programme: LiSyM: Liver Systems Medicine
Public web page: http://www.lisym.org
Start date: 1st Jan 2016
In one in five people with NAFLD, the functioning liver cells, the hepatocytes, are replaced by connective tissue. Eventually this fibrosis becomes irreversible. In this state the liver is like a ‘scar that never heals’. Through it, the liver loses many of its vital functions. LiSyM-Pillar II wants to know more about which factors promote fibrosis and the conditions under which fibrosis becomes irreversible How can fibrosis be diagnosed as early as possible? Researchers in the pillar are also ...
Programme: LiSyM: Liver Systems Medicine
Public web page: http://www.lisym.org/our-work/pillar-research
Start date: 1st Jan 2016
PBC scoring of liver fibrosis in 12 to 84 weeks old Abcb4ko mice. Correlation analysis is based on Test z versus 12-weeks-old mice (PPTX 69 KB)
Creator: Seddik Hammad
Submitter: Seddik Hammad
Abcb4ko mouse age, gender and number. Experiment 1 was used to investigate chronic liver disease development and progression. Experiment 2 was performed to test the anti-fibrotic efficiency of Galunisertib. (PPTX 36 KB)
Creator: Seddik Hammad
Submitter: Seddik Hammad
Negative controls for IHC as used in this study. In the same staining batch, negative controls by omitting first antibodies were included. Scale bars are 100 µm. (PPTX 5991 KB)
Creator: Seddik Hammad
Submitter: Seddik Hammad
Body and liver weight as well as liver enzymes upon Galunisertib treatment in 26-weeks-old Abcb4ko mice. a–c mouse and liver weight, and liver as percentage of total body weight. No significant difference is present due to Galunisertib administration. d–f) liver enzymes in Galunisertib, vehicle and untreated mice. e) H&E staining across different groups. Scale bars are 200 µm. Data are means ± SD of 5–7 mice per group. N.S.: P > 0.05; *: P < 0.05; **: P < 0.01 compared with untreated ...
Creator: Seddik Hammad
Submitter: Seddik Hammad
Fig. S1 Liver cell proliferation, resident macrophage and leucocyte numbers upon Galunisertib treatment in 26-weeks-old Abcb4ko mice. a) Representative images of Ki-67 (proliferation marker), F4/80 (resident macrophages) and CD45 (leukocyte common marker) positive signals in liver tissues upon Galunisertib or vehicle administration. Scale bars are 100 µm. b and c) show numbers of proliferating hepatocytes and non-parenchymal cells, as indicated by Ki-67 positivity. d and e) quantification of F4/80 ...
Creator: Seddik Hammad
Submitter: Seddik Hammad
