Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver

Aim: Hepatocyte growth factor (HGF) ameliorates liver fibrosis/cirrhosis in animal models, while the participation of bone marrow‐derived cells (BMC) in the repair process of injured organs has recently been reported. In this study we investigated the roles of HGF and BMC in a remodeling process of liver fibrosis. Methods: C57BL/6 J mice were treated with carbon tetrachloride (CCl4) for 10 weeks. At week six, the mice underwent whole body irradiation and transplantation with bone marrow cells from syngenic LacZ‐transgenic mice. After the transplantation, gene transfer of HGF into skeletal muscles was performed once a week for four weeks. In the control group, sterile saline was injected. Results: HGF gene transfer ameliorated the CCl4‐induced liver fibrosis, accelerating recruitment of LacZ‐expressing cells into the liver. This phenomenon was accompanied byincreased gelatinase activity in the liver. A large number of the LacZ‐positive cells expressed markers of vascular endothelial cells, while some of them had a marker of macrophages. Expression of stromal cell‐derived factor (SDF)‐1 in the liver was upregulated around the central veins, especially in the HGF gene‐transferred animals, recruiting chemokine (C‐X‐C motif) receptor (CXCR) 4‐positive cells in this area. Conclusion: Transplanted BMC participate in the HGF‐induced remodeling process of liver fibrosis. The roles of HGF in this process include the recruitment of BMC, possibly through increased expression of SDF‐1 in part, as well as anti‐apoptotic, mitogenic and antifibrotic activities on liver cells.