Abstract
Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1) is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.
Highlights
Fibrosis is a consequence of chronic liver disease and may lead to cirrhosis and liver failure
We report that Proteinase activated receptor 1 (PAR1) is abundantly expressed along the septal scars and within the hepatic lobule, with expression increasing markedly after liver injury
The importance of PAR1 signalling in liver fibrogenesis has been shown in murine models of cholestatic and parenchymal liver injury, and PAR1 expression in human liver disease has been demonstrated [19,22,23,24]
Summary
Fibrosis is a consequence of chronic liver disease and may lead to cirrhosis and liver failure. Recent studies have clearly shown that the bone marrow (BM) can contribute to hepatic myofibroblast populations in murine models of liver injury and in patients with liver fibrosis [1,2,3,4]. BM-derived cells, such as macrophages, may aid liver recovery by assisting in fibrous matrix degradation via the production of matrix metalloproteinases and anti-inflammatory cytokines [9,10,11] Coagulation cascade proteinases, such as thrombin, play key roles in inflammation and fibrosis in multiple organs including the liver [12,13,14,15,16]. Doi:10.1371/journal.pone.0086241.t001 fibrotic liver injury using mice deficient in functional PAR1, we sought to investigate the mechanisms by which PAR1 signalling in BM-derived cells, in particular in macrophages, may influence liver fibrosis **used for fluorescence immunodetection of macrophages in conjunction with in situ hybridisation for Y chromosome. 1a kind gift from Dr Eleanor Mackie, Melbourne, Australia. doi:10.1371/journal.pone.0086241.t001 fibrotic liver injury using mice deficient in functional PAR1, we sought to investigate the mechanisms by which PAR1 signalling in BM-derived cells, in particular in macrophages, may influence liver fibrosis
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