A Transient Increase in C-myc Precedes the Transdifferentiation of Hepatic Stellate Cells to Myofibroblast-like Cells

Aims/background: Liver stellate cells are transdifferentiated to collagen-producing myofibroblast-like cells in vivo during liver injury or when placed in culture. The purpose of this study was to determine the presence of retinoids and the expression of the immediate early genes as they relate to the transdifferentiation of liver stellate cells in culture.

Methods: Rat liver stellate cells were studied immediately after isolation or sequentially after culture for varying periods of time. RNA was isolated and specific messages were determined by RT-PCR. Cells were also isolated for determination of retinoid autofluorescence and immunofluorescent staining with specific antibodies by laser confocal microscopy.

Results: c-fos message and immunoprotein were high in the freshly isolated cells prior to culture, while c-myc expression increased markedly after one day of culture. Both c-fos and c-myc gene expression decreased prior to the transdifferentiation of the cells to myofibroblast-like cells and to the increase in alpha 1(I) and alpha 2(I) collagen messages and collagen production. The presence of retinoid autofluorescence and retinoic acid receptor (RAR-alpha and RAR-beta) messages and RAR-beta immunoprotein persisted during initial transdifferentiation of the stellate cells.

Conclusions: This study shows a high initial level of c-fos expression and a transient increase in c-myc expression followed by a decrease to lower levels prior to transdifferentiation and collagen production by stellate cells. A total loss of retinoid autofluorescence or a decrease in RAR-alpha or RAR-beta are not required for initial transdifferentiation of stellate cells or collagen production.