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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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