Role of c-kit receptor tyrosine kinase in development of oval cells in the rat 2-acetylaminofluorene/partial hepatectomy model.

Oval cells that develop in the rat 2-acetylaminofluorene/partial hepatectomy (AAF/PH) model express the c-kit receptor tyrosine kinase (KIT) and its ligand, stem cell factor (SCF). We investigated the role of the SCF/KIT system in the development of oval cells using Ws/Ws rats, whose c-kit kinase activity was severely impaired owing to a small deletion in the kinase domain. On days 7, 9, and 13 after PH in the AAF/PH model, the development of oval cells was remarkably suppressed in Ws/Ws rats when compared with that of the control normal (+/+) rats. However, oval cells that developed in Ws/Ws rats expressed marker proteins of oval cells, such as alpha-fetoprotein (AFP), cytokeratin-19 (CK-19), and flt-3 receptor tyrosine kinase, similar to those of +/+ rats. Furthermore, labeling with [3H]-thymidine and immunostaining of Ki-67 showed that the proliferative activity of oval cells that developed in Ws/Ws rats was comparable with that of +/+ rats. The present results indicate that the signal transduction of the SCF/KIT system plays a crucial role in the development of oval cells, at least, in the rat AAF/PH model, and suggest that KIT-mediated signal transduction plays only a small role in determining the phenotype and in the proliferative activity of oval cells.