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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 fibrosisresistant 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 fibrosissusceptible 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.

Original languageEnglish
Pages (from-to)325-334
Number of pages10
JournalAmerican Journal of Pathology
Volume185
Issue number2
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Fingerprint

Sclerosing Cholangitis
Portal Hypertension
Liver Neoplasms
Fibrosis
Tumor Burden
Liver Cirrhosis
Portal Pressure
Procollagen
Inbred Strains Mice
Onions
Liver
Liver Diseases
Collagen
Skin
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

A new mdr2-/- mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer. / Ikenaga, Naoki; Liu, Susan B.; Sverdlov, Deanna Y.; Yoshida, Shuhei; Nasser, Imad; Ke, Qingen; Kang, Peter M.; Popov, Yury.

In: American Journal of Pathology, Vol. 185, No. 2, 01.01.2015, p. 325-334.

Research output: Contribution to journalArticle

Ikenaga, Naoki ; Liu, Susan B. ; Sverdlov, Deanna Y. ; Yoshida, Shuhei ; Nasser, Imad ; Ke, Qingen ; Kang, Peter M. ; Popov, Yury. / A new mdr2-/- mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer. In: American Journal of Pathology. 2015 ; Vol. 185, No. 2. pp. 325-334.
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