Expression of large tenascin-C splice variants by hepatic stellate cells/myofibroblasts in chronic hepatitis C.
OBJECTIVE
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 LI90 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 LI90 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.
El-Karef
Amro
A
Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Mie, Japan.
Kaito
Masahiko
M
Tanaka
Hideaki
H
Ikeda
Kazuo
K
Nishioka
Tomohiro
T
Fujita
Naoki
N
Inada
Hiroyasu
H
Adachi
Yukihiko
Y
Kawada
Norifumi
N
Nakajima
Yuji
Y
Imanaka-Yoshida
Kyoko
K
Yoshida
Toshimichi
T
D000199:Actins / Q000378:metabolism; D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D018604:Epitope Mapping; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D014644:Genetic Variation; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D019063:Tenascin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
D000199:Actins; D000911:Antibodies, Monoclonal; D019063:Tenascin