Basic fibroblast growth factor stimulates repair of wounded hepatocyte monolayer: modulatory role of protein kinase A and extracellular matrix.

The two important repair mechanisms after hepatocyte injury are proliferation and migration of the nearby healthy hepatocytes. Although previous studies have shown that basic fibroblast growth factor (bFGF) levels are markedly elevated after liver injury, the role of bFGF in the repair of the wounded hepatocytes is not well understood. The aim of this study was to delineate the role of bFGF in the repair of the wounded hepatocyte monolayers. Specifically, we examined the role of bFGF in cellular proliferation and migration of hepatocytes with an in vitro wound model. Standardized excisional wounds were created in clone 9 rat hepatocyte monolayers by a razor blade, and the extent of epithelial proliferation and migration was measured. After wound formation, bFGF (30 ng/mL) significantly stimulated proliferation of hepatocytes at the wound margin. bFGF also stimulated the migration of hepatocytes at the wound front. bFGF stimulation of hepatocyte migration correlated with increased formation of actin stress fibers and bFGF-receptor protein level. The bFGF stimulation of hepatocyte migration was abolished by various protein kinase A activating agents including 3-isobutyl-1-methylxanthine, 8-bromoadenosine-3', 5'-cyclic monophosphate, forskolin, and cholera toxin. In addition, protein kinase A activating agents almost completely prevented bFGF-induced actin stress fiber formation in the cells at the wound front. Varying the basement membrane composition of the extracellular matrix had a selective enhancing effect on the basal rates of hepatocyte migration (collagen IV > or = laminin > collagen I > fibronectin > control (plastic)). bFGF treatment resulted in a similar additive increase in hepatocyte migration across all coated surfaces studied. We conclude that bFGF promotes hepatocyte wound repair by stimulating both proliferation and migration of the hepatocyte at the margin of the wound.