Phenotypical modulation of liver fat-storing cells by retinoids. Influence on unstimulated and growth factor-induced cell proliferation

In conditions of chronic liver inflammation, liver fat-storing cells (FSC) differentiate into 'myofibroblast-like cells'. This transition is characterized by a gradual loss of vitamin A stores, and previous studies suggest a possible relationship between the intracellular retinoid content and the proliferative potential of this cell type. In the present study, we further characterized this aspect of FSC biology by monitoring ultrastructural changes and growth characteristics during several serial passages in culture. Our observations suggest that the complete transition to the 'myofibroblast-like phenotype' is paralleled by a sudden and remarkable increase in the growth rate. At this stage, cell growth appears rather independent from the presence of mitogens in the culture medium, suggesting cell transformation. Accordingly, the mitogenic effects of platelet-derived growth factor and epidermal growth factor appears reduced when compared to those observed in FSC retaining the original 'storing' phenotype. Incubation of vitamin A-depleted FSC with retinol and retinoic acid resulted in the partial recovery of intracellular retinoid stores and in a significant reduction of basal growth rate and basal and growth factor-induced DNA synthesis. In summary, these in vitro observations suggest that intracellular retinoids play a central role in the control of unstimulated and growth factor-induced FSC proliferation and may help understand in vivo mechanisms leading to liver fibrosis.