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

Abstract

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. (HEPATOLOGY 2011;)

Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

“…Infusion of bone marrow‐derived macrophages has been shown to reduce hepatic fibrosis by recruiting endogenous macrophages and neutrophils 3. Administration of granulocyte colony‐stimulating factor enhanced migration of bone marrow cells into fibrotic liver and accelerated the regression of liver fibrosis 24.…”

“…However, the mechanism underlying the positive effect of MSCs or macrophages on cirrhosis remains unknown, although several possibilities have been considered; these include transdifferentiation of MSCs into hepatocyte‐like cells, secretion of factors that suppress activated stellate cells, modulation of immunity, resolution of fibrosis, and stimulation of hepatocyte proliferation. On the other hand, it has been shown that bone marrow‐derived macrophage delivery induced up‐regulation of a chemokine that recruits endogenous macrophages and neutrophils in the liver, improving fibrosis 3. Furthermore, hepatic macrophages have been reported to promote the neutrophil‐dependent resolution of fibrosis in cholestatic rat liver 29…”

“…Macrophages also play a central role for pathogenesis of chronic liver injury by phagocytosis of apoptotic liver cells, promoting inflammation, and producing matrix metalloproteinases (MMPs) that are responsible for the degradation of ECM 3. Hepatic macrophages are a heterogeneous cell population that includes the liver resident macrophages, Kupffer cells, and bone marrow‐derived macrophages 4.…”

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

“…Earlier reports that BMCs could themselves adopt an epithelial phenotype in the liver have proven to be unfounded (24). A recent study by us in a chronic liver injury model has shown infusion of BM-derived macrophages improves fibrosis and is associated with improved liver function (22). However, a direct effect of macrophages upon the DRs or HPCs themselves has not been shown.…”

“…Nonetheless, interpretation of a direct paracrine pathway from BM-derived cells to tissue progenitor cells is complicated during tissue injury by the association of local inflammation and tissue remodeling, processes that are affected by BM-derived cells (21,22) and that also indirectly influence tissue progenitor cell activation (23).…”