COEXPRESSION OF FLT-3 LIGAND FLT-3 AND SCF C-KIT SIGNAL-TRANSDUCTION SYSTEMS IN BILE-DUCT-LIGATED SL-MICE AND W-MICE/

Stem cell factor (SCF) and its receptor c-kit constitute an important signal transduction system regulating cell growth and differentiation in hematopoiesis, gametogenesis, and melanogenesis. Recently, we have demonstrated that both SCF and c-kit are expressed in the bile duct ep ithelial cells of the mt liver and are highly up-regulated during acti vation of the normally dormant hepatic stem cell compartment. In the p resent study, we used sl/sl(d) and w/w(v) mice, which have mutation of either SCF or c-kit, to study the possible involvement of the SCF/c-k it system in the bile duct proliferation. Bile duct ligation was perfo rmed to induce the Proliferation of bile duct epithelial cells. The tr anscripts for both SCF and c-kit were clearly increased after bile duc t ligation in both control and mutant mice. Moreover, both SI and W mi ce responded to the bile duct ligation, similar to the control mice, b y developing new bile ducts. Recently, a novel tyrosine kinase recepto r, flt-3 receptor, has been identified in the fetal liver. It has been reported that the flt-3 ligand (FL)/flt-3 system can synergize with t he SCF/c-kit system and stimulate the proliferation of hematopoietic c ells. Therefore, we hypothesized that the FL/flt-3 system might compen sate for the compromised SCF/c-kit system in the liver of SI and W mic e. The expression of both FL and flt-3 were significantly increased in bile-duct-ligated liver from both normal and mutant mice, and the tra nscripts for the flt-3 receptor were selectively located on bile duct epithelial cells. Based on these results, we postulate the existence o f a compensatory/additive function between the FL/flt-3 and the SCF/c- kit signal transduction systems in hepatic cell biology.