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(American Journal of Pathology. 2000;156:115-124.)
© 2000 American Society for Investigative Pathology

Regular Articles

Transforming Growth Factor-ß Initiates Wound Repair in Rat Liver through Induction of the EIIIA-Fibronectin Splice Isoform

Jacob George^*, Shao-Shean Wang^*, Ann-Marie Sevcsik^*, Michele Sanicola, Richard L. Cate, Victor E. Koteliansky and D. Montgomery Bissell^*

From the Liver Center and Department of Medicine,^*
University of California, San Francisco, California; and Biogen, Inc.,
Cambridge, Massachusetts

A prominent feature of the hepatic response to injury is production of a fetal isoform of fibronectin, a splice variant containing the EIIIA region, which appears very early after injury and derives from sinusoidal endothelial cells. Previous studies have shown that it is instrumental in initiating the cellular response to injury, specifically the conversion of resting stellate cells to myofibroblast-like cells. The present work describes the regulation of this change in fibronectin expression. Using sinusoidal endothelial cells from normal or injured liver in primary culture, we show that exogenous transforming growth factor ß (TGFß) stimulates [EIIIA]Fn expression. To assess the role of TGFß in vivo, we used a chimeric IgG containing the extracellular portion of the TGFß type II receptor as a competitive inhibitor of the cytokine. Administered to animals at the time of injury, the inhibitor reduced expression of [EIIIA]Fn mRNA by 50% as compared to controls (P < 0.01). There was a corresponding decrease in [EIIIA]Fn protein production as judged by immunohistochemistry. Cell fractionation experiments indicated that the changes observed in whole-liver extracts were localized to sinusoidal endothelial cells. We conclude that TGFß initiates wound repair in part by stimulating endothelial expression of [EIIIA]Fn. Results with the soluble inhibitor of the TGFß type II receptor suggest a novel strategy for modulating wound repair in vivo.

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