2. Academic Validation
  3. TGF-β2 silencing to target biliary-derived liver diseases

TGF-β2 silencing to target biliary-derived liver diseases

  • Gut. 2020 Sep;69(9):1677-1690. doi: 10.1136/gutjnl-2019-319091.
Anne Dropmann 1,  Steven Dooley 2,  Bedair Dewidar 1 3,  Seddik Hammad 1 4,  Tatjana Dediulia 1,  Julia Werle 1,  Vanessa Hartwig 1,  Shahrouz Ghafoory 5,  Stefan Woelfl 5,  Hanna Korhonen 6,  Michel Janicot 6,  Katja Wosikowski 6,  Timo Itzel 7,  Andreas Teufel 7,  Detlef Schuppan 8 9 10,  Ana Stojanovic 11,  Adelheid Cerwenka 11,  Stefanie Nittka 12,  Albrecht Piiper 13,  Timo Gaiser 14,  Naiara Beraza 15 16,  Malgorzata Milkiewicz 17,  Piotr Milkiewicz 18,  John G Brain 19,  David E J Jones 19,  Thomas S Weiss 20,  Ulrich M Zanger 21 22,  Matthias Ebert 23,  Nadja M Meindl-Beinker 2
Affiliations

Affiliations

  • 1 Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 2 Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany steven.dooley@medma.uni-heidelberg.de Nadja.Meindl-Beinker@medma.uni-heidelberg.de.
  • 3 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
  • 4 Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
  • 5 Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
  • 6 Isarna Therapeutics GmbH, Munchen, Germany.
  • 7 Hepatology and Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • 8 Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
  • 9 Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
  • 10 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • 11 Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM) and European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 12 Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany.
  • 13 Medizinische Klinik 1, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
  • 14 Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 15 Gut Microbes and Health Institute Strategic Programme, Quadram Institute, Norwich, UK.
  • 16 CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain.
  • 17 Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
  • 18 Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
  • 19 NIHR Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 20 Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany.
  • 21 Department of Molecular and Cell Biology, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • 22 Eberhard-Karls-University Tübingen, Tübingen, Germany.
  • 23 Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
PMID: 31992593 DOI: 10.1136/gutjnl-2019-319091
Abstract

Objective: TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.

Design: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.

Results: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed Antisense Oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.

Conclusions: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

Keywords

TGF-beta; cholestasis; fibrosis; primary biliary cirrhosis; primary sclerosing cholangitis.

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