The Role of Fibrocytes in Liver Fibrosis

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Chronic liver injury results in hepatic fibrosis, which is characterized by extensive deposition of extracellular matrix proteins (ECM), increased levels of TGF-¿1 and circulating endotoxin (lipopolysaccharide, LPS), and activation of collagen producing myofibroblasts. Development of liver fibrosis is accompanied by recruitment of bone marrow (BM)-derived fibrocytes, that are CD45 and collagen-a1(I) expressing cells, previously implicated in the pathogenesis of fibrosis in lungs, skin, and kidneys. We have demonstrated that fibrocytes contribute to liver fibrosis by comprising 4-6% of collagen producing cells in the fibrotic liver and differentiating into fibrogenic myofibroblasts. Despite of low numbers, our preliminary data suggest that inhibition of fibrocyte function(s) by the natural inhibitor Serum Amyloid P (SAP), results in the blockage of fibrocyte flux into fibrotic liver, and significantly attenuates liver fibrosis. Current proposal investigates the effect of SAP on liver fibrosis, fibrocyte recruitment and differentiation into myofibroblasts, and mediation of inflammatory signals in the course of liver fibrosis using two models of liver injury, carbontetrachloride (CCl4 and bile duct ligation (BDL). We anticipate that fibrocytes play an important role in pathogenesis of liver fibrosis (AIM 1). Therefore, fibrocytes may present an attractive target for anti-fibrotic therapy. To support our hypothesis, we developed a complimentary approach to study the role of fibrocytes in liver fibrosis. Using Cre-loxP recombination technique, we generate transgenic mice devoid of fibrocytes (AIM 2). Ablation of fibrocytes in vivo is achieved by overexpression of Diphtheria toxin-a (DTA) or receptor (DTR) in Collagen-a1(I)+CD45+ fibrocytes. Deletion of fibrocytes has not been reported, and will provide the invaluable insight into the role of fibrocytes in pathogenesis of liver fibrosis. We believe that fibrocytes may become a novel target for anti-fibrotic therapy. Futhermore, fibrocyte inhibitor SAP, which is used in clinical trals for lung and skin fibrosis, may present a potentially new treatment for patients with liver fibrosi. Here we determine the origin of BM-derived fibrocytes (hematopoietic or mesenchymal), and define their relationship to common myeloid progenitors (CMP) and monocytes (AIM 3). We predict that fibrocytes originate from c-kit+Sca-1+ hematopoietic stem cells, but developmentally precede CMP during hematopoiesis. In concordance, fibrocytes possess high plasticity, and in response to liver injury migrate to fibrotic liver, but also to spleen where they mediate antimicrobial response. It remains unclear how expression of collagen affects functions of fibrocytes. We address this question by generation of collagen-mutant fibrocytes, which downregulate collagen-a1(I) production (5'SL), or express a more stable uncleavable Col1a1rr protein (AIM 4). The functions of mutant fibrocytes are studied in vivo and compared to the wild type fibrocytes. We expect that mutant collagen-deficient fibrocytes exhibit a defect in transmigration, differentiation into myofibroblasts, while Col1a1rr-mutant fibrocytes are expected to possess a highly fibrogenic phenotype.