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Macrophage therapy for liver fibrosis and regenerationSJ ForbesDuring chronic liver injury there is deposition of excess collagen scar, and impaired liver regeneration from hepatic progenitor cells (HPCs) which regenerate both cholangiocytes and hepatocytes. We have found that endogenous hepatic macrophages are important for the reversal of liver fibrosis (1,2). Furthermore during hepatocyte regeneration from HPCs, macrophages control the differentiation of HPCs to hepatocytes. Macrophages phagocytose hepatocyte debris, inducing macrophage Wnt3a expression. This macrophages derived Wnt signalling in the HPC niche promotes HPC specification to hepatocytes (3). We have therefore tested macrophage cell therapy in chronic liver injury. Macrophage injection results in hepatic chemokine up-regulation and hepatic recruitment of endogenous macrophages and neutrophils to hepatic scars delivering MMP-13 and MMP-9 into the hepatic scar causing a significant reduction in hepatic fibrosis, increased the numbers of HPCs and increases serum albumin (4). We have also found that single injection of bone marrow or macrophages induces a significant activation of ductular reactions and HPCs in normal uninjured liver in a TWEAK/fn14 dependent manner (5). We are therefore developing macrophage therapy for liver cirrhosis in man. References:(1) Duffield JS, et al. J Clin Invest. 2005 Jan;115(1):56-65 (2) Ramachandran P, et al. Proc Natl Acad Sci USA. 2012 Nov 13;109(46):E3186-95 (3) Boulter L, et al. Nature Medicine 2012;18(4):572-9 (4) Thomas JA, et al. Hepatology. 2011;53(6):2003-15 (5) TG Bird et al. Proc Natl Acad Sci USA. 2013 In Press. |
