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American Journal of Pathology, Vol 150, 1179-1187, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Coexpression of flt-3 ligand/flt-3 and SCF/c-kit signal transduction system in bile-duct-ligated SI and W mice

M Omori, N Omori, RP Evarts, T Teramoto and SS Thorgeirsson
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-4255, USA.

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 epithelial cells of the rat liver and are highly up-regulated during activation of the normally dormant hepatic stem cell compartment. In the present study, we used sl/sld and w/wv mice, which have mutation of either SCF or c-kit, to study the possible involvement of the SCF/c-kit system in the bile duct proliferation. Bile duct ligation was performed to induce the proliferation of bile duct epithelial cells. The transcripts for both SCF and c-kit were clearly increased after bile duct ligation in both control and mutant mice. Moreover, both Sl and W mice responded to the bile duct ligation, similar to the control mice, by developing new bile ducts. Recently, a novel tyrosine kinase receptor, 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 the SCF/c-kit system and stimulate the proliferation of hematopoietic cells. Therefore, we hypothesized that the FL/flt-3 system might compensate for the compromised SCF/c-kit system in the liver of Sl and W mice. The expression of both FL and flt-3 were significantly increased in bile duct-ligated liver from both normal and mutant mice, and the transcripts for the flt-3 receptor were selectively located on bile duct epithelial cells. Based on these results, we postulate the existence of a compensatory/additive function between the FL/flt-3 and the SCF/c-kit signal transduction systems in hepatic cell biology.

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