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Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function.

TitleMacrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function.
Publication TypeJournal Article
Year of Publication2011
AuthorsThomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland SN, Ramachandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ
Date Published2011 Jun
KeywordsAnimals, Carbon Tetrachloride, Cell- and Tissue-Based Therapy, Chemokines, Disease Models, Animal, Female, Insulin-Like Growth Factor I, Liver, Liver Cirrhosis, Liver Function Tests, Liver Regeneration, Macrophage Colony-Stimulating Factor, Macrophages, Male, Mice, Serum Albumin, Tumor Necrosis Factors, Vascular Endothelial Growth Factor A

UNLABELLED: 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: Macrophage cell therapy improves clinically relevant parameters in experimental chronic liver injury. Paracrine signaling to endogenous cells amplifies the effect. The benefits from this single, defined cell type suggest clinical potential.

Alternate JournalHepatology
PubMed ID21433043
Grant ListG0600033 / / Medical Research Council / United Kingdom
G0700582 / / Medical Research Council / United Kingdom
G0901193 / / Medical Research Council / United Kingdom
G1000868 / / Medical Research Council / United Kingdom