Mouse models of primary sclerosing cholangitis: we just can’t get enough

Abstract

Primary sclerosing cholangitis (PSC) is a rare but devastating disease affecting the intra- and extrahepatic bile ducts, frequently progressing to end-stage liver disease. Patients develop peribiliary inflammation and fibrosis, leading to multifocal biliary strictures that evolve to biliary cirrhosis. PSC is frequently associated with inflammatory bowel disease and a high risk of cholangiocarcinoma development. The pathogenesis of this disease is not completely understood, and currently, there are no effective therapies beyond liver transplantation. The available experimental models of PSC do not fully reproduce the phenotype of the disease, and this is a major limitation for unraveling its pathogenic mechanisms and evaluating novel therapies. A recent study by Lukasova et al. proposed a new hypothesis on the pathogenesis of PSC. The relevance of their work is two-fold: (1) the authors provide preliminary evidence suggesting that the disruption of tight junctions in mouse biliary epithelium leads to a PSC-like phenotype; and (2) they provide the research community with a novel transgenic mouse model of the disease. Follow-up studies on this new mouse model are eagerly awaited.

Keywords

Primary sclerosing cholangitis / mouse models / liver fibrosis / tight junctions / kindlin-2 / phosphatidylcholine

References

[1] Karlsen TH,Thorburn D.Primary sclerosing cholangitis - a comprehensive review.J Hepatol2017;67:1298-323

[2] Trivedi PJ,Adams DH.Immunopathogenesis of primary biliary cholangitis, primary sclerosing cholangitis and autoimmune hepatitis: themes and concepts.Gastroenterology2024;166:995-1019

[3] Gleeson D,Trivedi PJ,Rea B.Surveillance for cholangiocarcinoma in patients with primary sclerosing cholangitis: can we be more proactive?.Frontline Gastroenterol2023;14:162-6 PMCID:PMC9933607

[4] Chapman MH,Hirschfield GM.British society of gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut2019;68:1356-78 PMCID:PMC6691863

[5] Kilanczyk E,Wunsch E.S-adenosyl-L-methionine (SAMe) halts the autoimmune response in patients with primary biliary cholangitis (PBC) via antioxidant and S-glutathionylation processes in cholangiocytes.Biochim Biophys Acta Mol Basis Dis2020;1866:165895

[6] Vierling JM.Animal models for primary sclerosing cholangitis.Best Pract Res Clin Gastroenterol2001;15:591-610

[7] Pollheimer MJ,Fickert P.Will we ever model PSC?.Clin Res Hepatol Gastroenterol2011;35:792-804

[8] Fickert P, Pollheimer MJ, Beuers U, et al; International PSC Study Group (IPSCSG). Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol 2014;60:1290-303. PMCID:PMC4517670

[9] Mariotti V,Spirli C,Strazzabosco M.Animal models of cholestasis: an update on inflammatory cholangiopathies.Biochim Biophys Acta Mol Basis Dis2019;1865:954-64

[10] Fickert P,Marschall HU.Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice.Am J Pathol2006;168:410-22 PMCID:PMC1606500

[11] Smit JJ,Oude Elferink RP.Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.Cell1993;75:451-62 PMCID:PMC295363

[12] Fickert P,Wagner M.Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.Gastroenterology2004;127:261-74

[13] Liu SP,Zhao ZB.Animal models of autoimmune liver diseases: a comprehensive review.Clin Rev Allergy Immunol2020;58:252-71

[14] Latasa MU,Fernández-Barrena MG.Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice.PLoS One2010;5:e15690 PMCID:PMC3012093

[15] Halilbasic E,Fickert P.Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2-/- mice†‡§.Hepatology2009;49:1972-81 PMCID:PMC3569724

[16] Hochrath K,Geisel J.Vitamin D modulates biliary fibrosis in ABCB4-deficient mice.Hepatol Int2014;8:443-52 PMCID:PMC4148166

[17] Rosenberg N,Lanton T.Combined hepatocellular-cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL-6 trans-signaling.J Hepatol2022;77:1631-41

[18] Arechederra M.Hepatic progenitor cells, senescence and IL-6 as the main players in combined hepatocellular-cholangiocarcinoma development.J Hepatol2022;77:1479-81

[19] Gao RY,Orlicky DJ.Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis.Mucosal Immunol2021;14:479-90 PMCID:PMC7954872

[20] Gauss A,Lehmann WD.Biliary phosphatidylcholine and lysophosphatidylcholine profiles in sclerosing cholangitis.World J Gastroenterol2013;19:5454-63 PMCID:PMC3761098

[21] Stremmel W,Weiskirchen R.The neglected biliary mucus and its phosphatidylcholine content: a putative player in pathogenesis of primary cholangitis-a narrative review article.Ann Transl Med2021;9:738 PMCID:PMC8106090

[22] Ehehalt R,Erben G.Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoElectrospray-tandem mass spectrometry.Scand J Gastroenterol2004;39:737-42

[23] Stremmel W,Gan-Schreier H,Bach M.Phosphatidylcholine passes through lateral tight junctions for paracellular transport to the apical side of the polarized intestinal tumor cell-line CaCo2.Biochim Biophys Acta2016;1861:1161-9

[24] Stremmel W,Weiskirchen R.Phosphatidylcholine passes by paracellular transport to the apical side of the polarized biliary tumor cell line Mz-ChA-1.Int J Mol Sci2019;20:4034 PMCID:PMC6720464

[25] Stremmel W,Schneider MJ.Genetic mouse models with intestinal-specific tight junction deletion resemble an ulcerative colitis phenotype.J Crohns Colitis2017;11:1247-57 PMCID:PMC5881657

[26] Sakisaka S,Taniguchi E.Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis.Hepatology2001;33:1460-8

[27] Rao RK.Bile duct epithelial tight junctions and barrier function.Tissue Barriers2013;1:e25718 PMCID:PMC3783222

[28] Lukasova M,Weiskirchen R.Onion-skin type of periductular sclerosis in mice with genetic deletion of biliary kindlin-2 as tight junction stabilizer: a pilot experiment indicating a primary sclerosing cholangitis (PSC) phenotype.Metab Target Organ Damage2024;4:36

[29] Wang W,Markovic V.Role of Kindlin-2 in cancer progression and metastasis.Ann Transl Med2020;8:901 PMCID:PMC7396786

[30] der Veen JN, Kennelly JP, Wan S, Vance JE, Vance DE, Jacobs RL. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease.Biochim Biophys Acta Biomembr2017;1859:1558-72

[31] Ismail IT,Helal M,El-Said H.Remodeling lipids in the transition from chronic liver disease to hepatocellular carcinoma.Cancers2020;13:88 PMCID:PMC7795670

[32] Korbecki J,Kupnicka P.Biochemistry and diseases related to the interconversion of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine.Int J Mol Sci2024;25:10745 PMCID:PMC11477190

[33] Sánchez V,Brandt A,Staltner R.Oral supplementation of phosphatidylcholine attenuates the onset of a diet-induced metabolic dysfunction-associated steatohepatitis in female C57BL/6J Mice.Cell Mol Gastroenterol Hepatol2024;17:785-800 PMCID:PMC10966192

[34] Won TJ,Lee HS.Injection of phosphatidylcholine and deoxycholic acid regulates gene expression of lipolysis-related factors, pro-inflammatory cytokines, and hormones on mouse fat tissue.Food Chem Toxicol2013;60:263-8

[35] Ishikado A,Yamane K.Soy phosphatidylcholine inhibited TLR4-mediated MCP-1 expression in vascular cells.Atherosclerosis2009;205:404-12

[36] Reichert MC.ABCB4 gene aberrations in human liver disease: an evolving spectrum.Semin Liver Dis2018;38:299-307