Role of C– Kit Receptor Tyrosine Kinase in Development of Oval Cells in the Rat 2–Acetylaminofluorene/Partial Hepatectomy Model

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Abstract
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 α–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.