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

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. In this study, CXCR4 conditionally targeted mice were used to analyze the role of SDF-1 in chronically damaged liver. Chronic liver damage was induced in MxCre CXCR4(f/null) mice and the control MxCre CXCR4(f/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. 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-alpha, and alpha-SMA. 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.