TY - JOUR
T1 - A new mdr2-/- mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer
AU - Ikenaga, Naoki
AU - Liu, Susan B.
AU - Sverdlov, Deanna Y.
AU - Yoshida, Shuhei
AU - Nasser, Imad
AU - Ke, Qingen
AU - Kang, Peter M.
AU - Popov, Yury
N1 - Funding Information:
Supported by an institutional grant from the Department of Medicine, Beth Israel Deaconess Medical Center (Y.P.).
Publisher Copyright:
Copyright © 2015 American Society for Investigative Pathology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922323884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922323884&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2014.10.013
DO - 10.1016/j.ajpath.2014.10.013
M3 - Article
C2 - 25478810
AN - SCOPUS:84922323884
VL - 185
SP - 325
EP - 334
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 2
ER -
