Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis

BACKGROUND/AIMS: Hepatic stellate cells (HSCs) play a key role in hepatic fibrogenesis. However, their origin is still unknown. We tested the hypothesis that bone marrow (BM) contributes to the population of HSCs. METHODS: Chimeric mice transplanted with donor BM from collagen alpha1(I)-GFP+ reporter mice were subjected to the bile duct ligation (BDL)-induced liver injury. RESULTS: In response to injury, BM-derived collagen-expressing GFP+ cells were detected in liver tissues of chimeric mice. However, these cells were not activated HSCs in that they did not express alpha-smooth muscle actin or desmin and could not be isolated with the HSC fraction. Meanwhile, the majority of these BM-derived cells co-expressed collagen-GFP+ and CD45+, suggesting that these cells represent a unique population of fibrocytes. Consistent with their lymphoid origin, the number of GFP+CD45+ fibrocytes found in BM and spleen of chimeric mice increased in response to injury. Fibrocytes cultured in the presence of TGF-beta1 differentiated into SMA+desmin+ collagen-producing myofibroblasts, potentially contributing to liver fibrosis. CONCLUSIONS: In response to the BDL-induced liver injury: (i) HSCs do not originate in the BM; (ii) collagen-producing fibrocytes are recruited from the BM to damaged liver.