Clinical studies of bone marrow (BM)
cell therapy for
liver cirrhosis are under way but the mechanisms of benefit remain undefined. Cells of the monocyte-macrophage lineage have key roles in the development and resolution of
liver fibrosis. Therefore, we tested the
therapeutic effects of these cells on murine
liver fibrosis. Advanced
liver fibrosis was induced in female mice by chronic administration of
carbon tetrachloride. Unmanipulated, syngeneic macrophages, their specific BM precursors, or unfractionated BM cells were delivered during liver injury.
Mediators of inflammation,
fibrosis, and regeneration were measured. Donor cells were tracked by sex-mismatch and
green fluorescent protein expression. BM-derived macrophage (BMM) delivery resulted in early
chemokine up-regulation with hepatic recruitment of endogenous macrophages and neutrophils. These cells delivered matrix metalloproteinases-13 and -9, respectively, into the hepatic
scar. The effector cell infiltrate was accompanied by increased levels of the antiinflammatory
cytokine interleukin 10. A reduction in hepatic myofibroblasts was followed by reduced
fibrosis detected 4 weeks after macrophage infusion.
Serum albumin levels were elevated at this time. Up- regulation of the liver progenitor cell
mitogen tumor necrosis factor-like weak inducer of apoptosis (TWEAK) preceded expansion of the progenitor cell compartment. Increased expression of colony stimulating factor-1,
insulin-like growth factor-1, and
vascular endothelial growth factor also followed BMM delivery. In contrast to the effects of differentiated macrophages,
liver fibrosis was not significantly altered by the application of macrophage precursors and was exacerbated by whole BM.
CONCLUSION: