Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs.

ABSTRACT

BACKGROUND: Using the dimethylnitrosamine (DMN) rat model of induced fibrosis, we investigated whether transfer of in vitro-expanded endothelial progenitor cells (EPCs) could reconstitute liver tissue and protect against liver fibrosis. MATERIALS AND METHODS: Low-density, adherent, rat bone marrow-derived mononuclear cells were cultured for one week in medium supporting the growth of chemokine (C-X-C motif) receptor 4 (CXCR4)-positive EPCs that were used for transplantation. Test rats were treated with weekly intraperitoneal injections of DMN over a period of 4 weeks. During that period, the rats were also transplanted weekly with in vivo-expanded EPCs. RESULTS: Transplanted CXCR4-positive expanded EPCs entered around the portal tracts, fibrous septa and hepatic sinusoids, locations at which stromal cell-derived factor 1 (SDF-1), a ligand attracting CXCR4-positive cells, was expressed nearby. In EPC-transplanted rats, we observed suppression of liver fibrogenesis, reduced deposition of type I collagen and fibronectin, fewer α-smooth muscle actin-positive cells and lower expression of transforming growth factor (TGF)-ß. The expression of growth factors promoting hepatic regeneration (hepatocyte growth factor, transforming growth factor-α (TGF-α), epidermal growth factor and vascular endothelial growth factor) was significantly increased in EPC-transplanted rats, resulting in hepatocyte proliferation. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Liver function tests of transaminase, total bilirubin, total protein and albumin demonstrated that normal levels were maintained in EPC-transplanted rats. CONCLUSIONS: EPC transplantation effectively promotes the remodelling of tissues damaged by liver fibrosis; it can also reconstitute sinusoids in chronic liver injury.