Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat.

Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes in vitro. The receptor for HGF has recently been characterized as the product of the proto-oncogene c-met. We have examined the possible involvement of HGF in hepatic growth and differentiation in the rat. The experimental systems used were acetylaminofluorene treatment combined with partial hepatectomy to induce proliferation and differentiation of oval cells in adult liver and the pre- and postnatal liver. In the acetylaminofluorene model, Northern blot analysis showed that level of HGF transcripts increased one day after partial hepatectomy, reached a peak by day 6, were maintained at that level until day 13, and then declined, reaching normal level at 20 days. The expression of c-met also increased gradually, reached a peak around 9 to 13 days after partial hepatectomy, at which time oval cell proliferation was most prominent. In the developing liver, an elevated level of HGF transcripts was found between 4 and 21 days after birth. The expression of c-met also slightly increased at the same time. In situ hybridization showed that the transcripts for HGF were localized in desmin-positive Ito cells, whereas the transcripts for c-met were strongly expressed by oval cells. We have shown earlier that Ito cells and oval cells proliferate simultaneously and exist in close proximity in the acetylaminofluorene model and that Ito cells are a primary source of growth factors such as transforming growth factor-alpha and acidic fibroblast growth factors. The data presented here suggest that HGF is, in combination with other growth factors, involved in the proliferation and differentiation of oval cells via a paracrine mechanism.