Expression of large tenascin-C splice variants by hepatic stellate cells/myofibroblasts in chronic hepatitis C

Background/Aims: Earlier studies have suggested involvement of tenascin-C (TN-C) in liver fibrosis. Here, we examined expression of TN-C variants and types of alternatively spliced fibronectin-type III (FNIII) repeats in chronic hepatitis. Methods: Using three monoclonal antibodies against TN-C variants, immunohistochemical staining was performed and the correlation with histological parameters of chronic hepatitis C was examined. The cellular source was also determined and variant expression and their types were tested using isolated rat hepatic stellate cells (HSCs), liver myofibroblasts, and/or L190 cells. Results: Large variants were not expressed in normal liver, but were up-regulated in chronic hepatitis, especially at sites of interface hepatitis and confluent necrosis, showing stronger correlations between staining intensity and these than with other parameters or fibrosis. TN-C deposition was closely correlated with increase in the number of alpha-smooth muscle actin-positive cells, i.e. activated HSCs/myofibroblasts, and in situ hybridization showed TN-C mRNA signals in the cells. Activated HSCs and myofibroblasts in culture highly expressed large variants of TN-C. In L190 cells, sequencing of large variants revealed that the FNIII repeats D and A1/A4, followed by B, were preferentially included. Conclusions: TN-C and its variants are produced by HSCs/myofibroblasts, suggesting important roles in liver fibrogenesis. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.