Mitogenic effect of transforming growth factor-beta 1 on human Ito cells in culture: evidence for mediation by endogenous platelet-derived growth factor.

We assessed the effect of transforming growth factor-beta 1 on the proliferation of human Ito cells. Ito cells in their myofibroblastlike phenotype were grown from explants of human liver and were characterized with electron microscopy and positive immunostaining for desmin and smooth muscle alpha-actin. Transforming growth factor-beta 1 was mitogenic for human Ito cells whatever the culture conditions, although it was, as previously described, inhibitory of growth for rat Ito cells. The mitogenic effect of transforming growth factor-beta 1 was likely due to induction of autocrine platelet-derived growth factor chain secretion by Ito cells themselves because (a) the mitogenic effect of transforming growth factor-beta 1 was blocked by specific platelet-derived growth factor antibodies, (b) transforming growth factor-beta 1 increased platelet-derived growth factor-A chain messenger RNA expression and platelet-derived growth factor-AA secretion by human Ito cells and (c) human Ito cells expressed the alpha-type platelet-derived growth factor-A receptor messenger RNA. Exogenous platelet-derived growth factor-AA was also mitogenic for human Ito cells, mimicking the effect of transforming growth factor-beta 1. Our data suggest that results obtained with rat Ito cells must be extrapolated with caution to human ones. The mitogenic effect of transforming growth factor-beta 1 on human Ito cells probably has pathophysiological relevance because transforming growth factor-beta 1 has been demonstrated in vivo at sites of active liver fibrogenesis.