A New Mdr2−/− Mouse Model of Sclerosing Cholangitis with Rapid Fibrosis Progression, Early-Onset Portal Hypertension, and Liver Cancer

• Published in: The American journal of pathology Vol. 185; no. 2; pp. 325 - 334
• Main Authors: Ikenaga, Naoki, Liu, Susan B, Sverdlov, Deanna Y, Yoshida, Shuhei, Nasser, Imad, Ke, Qingen, Kang, Peter M, Popov, Yury
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2015
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - deficiency; ATP-Binding Cassette Sub-Family B Member 4; Cholangitis, Sclerosing - genetics; Cholangitis, Sclerosing - metabolism; Cholangitis, Sclerosing - pathology; Disease Models, Animal; Hypertension, Portal - genetics; Hypertension, Portal - metabolism; Hypertension, Portal - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Pathology; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2014.10.013

We previously characterized the Mdr2 ( Abcb4 )−/− mouse as a reproducible model of chronic biliary liver disease. However, it demonstrates relatively slow fibrosis progression, possibly due to its fibrosis-resistant genetic background. We aimed to improve the model by moving it onto a fibrosis-susceptible background. We generated novel BALB/c. Mdr2−/− mouse via genetic backcross onto highly fibrosis-susceptible BALB/c substrain, identified in inbred mouse strain screening. Liver fibrosis, portal pressure, and hepatic tumor burden in BALB/c. Mdr2−/− mice were studied up to 1 year of age in direct comparison to parental strain FVB. Mdr2−/− . BALB/c. Mdr2−/− mice developed periductular onion-skin type fibrotic lesions and pronounced ductular reaction starting from 4 weeks of age. Compared to parental strain, BALB/c. Mdr2−/− mice demonstrated dramatically accelerated liver fibrosis, with threefold increase in collagen deposition and bridging fibrosis/early signs of cirrhosis at 12 weeks. This was accompanied by early-onset severe portal hypertension and twofold to fourfold increase in profibrogenic transcripts Col1a1 [procollagen α1(I)], Tgfb1 , and Timp1 . Primary liver cancers in BALB/c. Mdr2−/− developed earlier, with greater tumor burden compared to FVB. Mdr2−/− . BALB/c. Mdr2−/− mice have unprecedented degree and rapidity of hepatic fibrosis progression and clinically relevant cirrhosis complications, such as early-onset portal hypertension and primary liver cancers. This new model will facilitate development of antifibrotic drugs and studies into mechanisms of biliary fibrosis progression.