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Increased Susceptibility to Severe Chronic Liver Damage in CXCR4 Conditional Knock-Out Mice

Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

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.

Aims

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 CXCR4f/null mice and the control MxCre CXCR4f/wt mice by CCl4. 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 CXCR4f/null mice than MxCre CXCR4f/wt mice. The number of cytokeratin-positive cells and the area of fibrosis were also increased in the MxCre CXCR4f/null mice. The expression of mRNAs for several markers related to hepatic damage and regeneration was also increased in the liver of MxCre CXCR4f/null mice, including primitive HPC marker prominin-1, MMP9, TNF-α, and α-SMA.

Conclusions

MxCre CXCR4f/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.

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Abbreviations

SDF-1:

Stromal cell-derived factor-1

CXCR4:

C-X-C chemokine receptor type 4

HGF:

Hepatocyte growth factor

bFGF:

Basic fibroblast growth factor

EGF:

Epidermal growth factor

OSM:

Oncostatin M

HIV:

Human immunodeficiency virus

pIpC:

Poly(I)-poly(C)

PBS:

Phosphate-buffered saline

FACS:

Fluorescence-activated cell sorter

FITC:

Fluorescein isothiocyanate

PCR:

Polymerase chain reaction

ALB:

Albumin

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

VEGF:

Vascular endothelial growth factor

AFP:

α-Fetoprotein

NCAM:

Neural cell adhesion molecule

DLK-1:

Delta-like 1 homolog

G-6-p:

Glucose-6-phosphate

CPS1:

Carbamoyl phosphate synthetase 1

cyp:

Cytochrome P450

α-SMA:

α Smooth muscle actin

TNF-α:

Tumor necrosis factor-α

TGF-β:

Transforming growth factor-β

MMP:

Matrix metalloproteinase

TIMP:

Tissue inhibitors of metalloproteinases

GAPDH:

Glyceraldehydes-3-phosphate dehydrogenase

TGF:

Transforming growth factor

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Acknowledgments

We thank Professor Rajewsky (Harvard Medical School) and Professor Lichtenberg (University of Cologne) for providing MxCre mice. This research was supported by Tsukada memorial grant, by a Grant-in Aid for Young Scientists (B, 22790634) of The Ministry of Education, Culture, Sports, Science and Technology and by a Grant for Promotion of Niigata University Research Project.

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Correspondence to Atsunori Tsuchiya.

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Tsuchiya, A., Imai, M., Kamimura, H. et al. Increased Susceptibility to Severe Chronic Liver Damage in CXCR4 Conditional Knock-Out Mice. Dig Dis Sci 57, 2892–2900 (2012). https://doi.org/10.1007/s10620-012-2239-8

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  • DOI: https://doi.org/10.1007/s10620-012-2239-8

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