A new Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer

Naoki Ikenaga; Susan B Liu; Deanna Y Sverdlov; Shuhei Yoshida; Imad Nasser; Qingen Ke; Peter M Kang; Yury Popov

doi:10.1016/j.ajpath.2014.10.013

A new Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer

Am J Pathol. 2015 Feb;185(2):325-34. doi: 10.1016/j.ajpath.2014.10.013. Epub 2014 Dec 2.

Authors

Naoki Ikenaga¹, Susan B Liu¹, Deanna Y Sverdlov¹, Shuhei Yoshida¹, Imad Nasser², Qingen Ke³, Peter M Kang³, Yury Popov⁴

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
² Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
³ Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
⁴ Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: ypopov@bidmc.harvard.edu.

PMID: 25478810
DOI: 10.1016/j.ajpath.2014.10.013

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / deficiency*
ATP-Binding Cassette Sub-Family B Member 4
Animals
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
Tissue Inhibitor of Metalloproteinase-1 / genetics
Tissue Inhibitor of Metalloproteinase-1 / metabolism
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism

Substances

ATP Binding Cassette Transporter, Subfamily B
Tgfb1 protein, mouse
Timp1 protein, mouse
Tissue Inhibitor of Metalloproteinase-1
Transforming Growth Factor beta1