Schulze, S.; Keshvari, S.; Miller, G.; Bridle, K.; Hume, D. A.; Irvine, K. M.

Background and Aims: In the context of hepatobiliary and liver transplant surgery, ischemia-reperfusion (I/R) injury can occur due to temporary interruption of blood flow to the organ followed by a potentially damaging inflammatory response to reperfusion. As macrophages can promote liver growth and resolution of chronic liver injury and fibrosis, we tested the hypothesis that stimulation of monocytes and macrophages with Colony Stimulating Factor 1 (CSF1) could promote liver repair after I/R injury. Methods: We investigated the impact of perisurgical treatment with a long-circulating CSF1-Fc conjugate on liver injury and hepatocyte proliferation after 70% ischemia for 60 minutes at 6 h, 48 h and 7 days post reperfusion in rats. Circulating and liver tissue monocyte and macrophage subsets in the ischaemic and oxygenated lobes were assessed using quantitative PCR and flow cytometry. Results: CSF1-Fc treatment did not affect the extent of hepatocellular injury post-reperfusion, as indicated by serum transaminases. Liver I/R injury, especially necrotic area, was reduced in CSF1-Fc-treated rats 48 h post-surgery. This was associated with increased accumulation of macrophages in both the oxygenated and ischemic lobes, and peri-necrotic zone localization in the ischemic lobe. CSF1-Fc treatment also promoted liver growth, associated with increased parenchymal and non-parenchymal cell proliferation. CSF1-Fc increased the abundance of CD43+ non-classical monocytes, consistent with the role of CSF1 signaling in monocyte maturation, and increased CD163 expression on mature macrophages. Conclusion: This study suggests CSF1 stimulation drives monocytes/macrophages towards a pro-regenerative response and perisurgical CSF1 treatment might augment liver regeneration in patients undergoing liver resection.