Increased susceptibility to severe chronic liver damage in CXCR4 conditional knock-out mice.
BACKGROUND
The chemokine SDF-1 and its receptor CXCR4 are essential for the proper functioning of multiple organs. In the liver, cholangiocytes and hepatic progenitor cells (HPCs) are the main cells that produce SDF-1, and SDF-1 is thought to be essential for HPC-stimulated liver regeneration.


OBJECTIVE
In this study, CXCR4 conditionally targeted mice were used to analyze the role of SDF-1 in chronically damaged liver.


METHODS
Chronic liver damage was induced in MxCre CXCR4(f/null) mice and the control MxCre CXCR4(f/wt) mice by CCl(4). Serum markers were analyzed to assess liver function and damage, the number of cytokeratin-positive cells as a measure of HPCs, and the extent of liver fibrosis. Additional parameters relating to liver damage, such as markers of HPCs, liver function, MMPs, and TIMPs were measured by real-time PCR.


RESULTS
Serum ALT was significantly higher in MxCre CXCR4(f/null) mice than MxCre CXCR4(f/wt) mice. The number of cytokeratin-positive cells and the area of fibrosis were also increased in the MxCre CXCR4(f/null) mice. The expression of mRNAs for several markers related to hepatic damage and regeneration was also increased in the liver of MxCre CXCR4(f/null) mice, including primitive HPC marker prominin-1, MMP9, TNF-α, and α-SMA.


CONCLUSIONS
MxCre CXCR4(f/null) mice were susceptible to severe chronic liver damage, suggesting that SDF-1-CXCR4 signals are important for liver regeneration and preventing the progression of liver disease. Modulation of SDF-1 may therefore be a promising treatment strategy for patients with chronic liver disease.
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. atsunori@med.niigata-u.ac.jp
Atsunori
A
Tsuchiya
Michitaka
M
Imai
Hiroteru
H
Kamimura
Masaaki
M
Takamura
Satoshi
S
Yamagiwa
Tatsuki
T
Sugiyama
Minoru
M
Nomoto
Toshio
T
Heike
Takashi
T
Nagasawa
Tatsutoshi
T
Nakahata
Yutaka
Y
Aoyagi
D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002908:Chronic Disease; D004198:Disease Susceptibility; D005434:Flow Cytometry; D008107:Liver Diseases / Q000378:metabolism*; D008111:Liver Function Tests; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000378:metabolism
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4