A Blood-to-Liver CXCL12 Concentration Gradient Parallels Increasing Fibrocytes and Liver Fibrosis in a Murine Model

Abstract

Purpose: Fibrocytes are circulating hematopoietic cells that home to sites of tissue injury via a chemokine gradient and promote fibrosis in several models of injury. Whether fibrocytes contribute to liver fibrosis has not been examined to date. CXCL12 binds to the chemokine receptor CXCR4 expressed on fibrocytes, potentially enabling their fibrogenic action in the liver. To better understand this association, we performed a pilot study in an established preclinical murine model of liver fibrosis. The use of this model allowed us to assess the kinetics and magnitude of fibrocyte presence in the bone marrow, blood, and liver of mice with developing hepatic fibrosis. We further postulated that a liver-blood CXCL12 concentration gradient contributed to fibrocyte trafficking to injured liver. Methods: We used an established 0.1% DDC model of liver fibrosis. A cohort of 6-8 week old female C57BL/6 mice received a diet of either DDC or control chow for 6 weeks. At weekly intervals, blood and liver were assessed for fibrocyte number and phenotype and concentration of CXCL12, and extent of liver fibrosis. Statistical differences between the DDC chow fed and control chow fed groups were assessed by linear regression. Results: Liver collagen deposition increased progressively 9-fold through week 6 in the DDC chow-fed group as compared to the control group (p<.01). There was a progressive, parallel increase in the number of fibrocytes and the liver-blood concentration gradient of CXCL12 between the DDC chow-fed as compared to control mice through (p <.001). There was no statistically significant increase in fibrocytes or the CXCL12 concentration gradient in the control chow fed mice. Conclusion: These data demonstrate that in a murine model of liver fibrosis, the number of blood and liver fibrocytes increase in parallel with progressive fibrosis, and correlate with a blood-to-liver CXCL12 concentration gradient.