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Delineating cell type, mechanism, consequences and targeting of TGF-β2 expression in biliary liver disease
The transforming growth factor (TGF)-β is well known as strong cell fate decision factor in the liver, when acute or chronic damage occurs and during liver disease progression of any etiology. 95% of current knowledge built on TGF-β1 related data and describe the cytokine as, among others, activator of hepatic stellate cells for matrix deposition and scarring, therewith major driver of fibrogenesis, as double edged tumor suppressor or tumor promoter in liver cancer, as well as modulator of the inflammatory response (although the latter is still not thoroughly delineated).
We now could show that in cholestatic or biliary liver diseases in mice and patients, the TGF-β2 isoform has a predominant role over TGF-β1, and we demonstrated that silencing of TGF-β2 effects with antisense oligonucleotides (AONs) in this liver disease setting has significant antifibrotic, regenerative and immune modulating effects.
To get further and more detailed insight, in the present project we aim to dissect the role of TGF-β2 in much detail and further develop its targeting as a future therapeutic approach for this rare but devastating liver disease. Specifically, we will (1) determine the liver cell type induced to express TGFβ2 in a mouse model of cholestatic liver disease, the ABCB4KO mouse, and in patients with primary sclerosing cholestasis (PSC), and (2) identify cytokine(s), stressors and pathway(s) leading to TGF-β2 expression induction;
(3) In another study, we will provide a time and space resolved dissection of cellular and tissue responses upon acute and chronic TGF-β2 delivery in healthy mice and ABCB4KO mice during disease progression, with special emphasis on a modulatory effect of the inflammatory response;
(4) Next, we aim at discriminating the cellular response of TGF-β2 vs TGF-β1 in different liver cells, and especially inflammatory cell types. Findings in mice will be translated to PSC patients.
Finally, since PSC is a risk factor for the deadly cholangiocarcinoma (CCA) and TGF-β2 have been shown upregulated in intrahepatic (iCCA), we will a potential therapeutic effect of targeting TGF-β2 in iCCA patient derived organoids. We are convinced that discussing the project progress in the MI3 consortium and collaborate with PIs of the network, will help to drive the project to top level.
Dropmann A, Dooley S, Dewidar B, Hammad S, Dediulia T, Werle J, Hartwig V, Ghafoory S, Woelfl S, Korhonen H, Janicot M, Wosikowski K, Itzel T, Teufel A, Schuppan D, Stojanovic A, Cerwenka A, Nittka S, Piiper A, Gaiser T, Beraza N, Milkiewicz M, Milkiewicz P, Brain JG, Jones DEJ, Weiss TS, Zanger UM, Ebert M, Meindl-Beinker NM. (2019) TGF-β2 Silencing to Target Biliary-Derived Liver Diseases. GUT, 2020 Jan 28, DOI: 10.1136/gutjnl-2019-319091
Dropmann A, Dediulia T, Breitkopf-Heinlein K, Korhonen H, Janicot M, Weber SN, Thomas M, Piiper A, Bertran E, Fabregat I, Abshagen K, Hess J, Angel P, Coulouarn C, Dooley S, Meindl-Beinker NM. TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget 2016;7(15):19499-518.
Dewidar B, Meyer C,Dooley S, Meindl-Beinker N. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells. 2019 Nov 11;8(11):1419. doi: 10.3390/cells8111419.
Fouassier L, Marzioni M, Afonso MB, Dooley S, Gaston K, Giannelli G, Rodrigues CMP, Lozano E, Mancarella S, Segatto O, Vaquero J, Marin JJG, Coulouarn C. Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance. Liver Int. 2019 May;39 Suppl 1:43-62. doi: 10.1111/liv.14102.
Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P, Dooley S. Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol. 2013 Mar 1;304(5):G449-68. doi: 10.1152/ajpgi.00199.2012. Epub 2012 Dec 28.
Dooley S, ten Dijke P. TGF-β in progression of liver disease. Cell Tissue Res. 2012 Jan;347(1):245-56. doi: 10.1007/s00441-011-1246-y. Epub 2011 Oct 19.
Meindl-Beinker NM, Matsuzaki K, Dooley S. TGF-β signaling in onset and progression of hepatocellular carcinoma. Dig Dis. 2012;30(5):514-23. doi: 10.1159/000341704. Epub 2012 Oct 24.
Prof. Dr. Steven Dooley