EXPRESSION OF HEPATOCYTE GROWTH-FACTOR AND C-MET GENES DURING HEPATICDIFFERENTIATION AND LIVER DEVELOPMENT IN THE RAT

Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocy tes 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. T he experimental systems used were acetylaminofluorene treatment combin ed with partial hepatectomy to induce proliferation and differentiatio n of oval cells in adult liver and the pre- and postnatal liver. In th e acetylaminofluorene model, Northern blot analysis showed that level of HGF transcripts increased one day after partial hepatectomy, reache d a peak by day 6, were maintained at that level until day 13, and the n declined, reaching normal level at 20 days. The expression of c-met also increased gradually, reached a peak around 9 to 13 days after par tial hepatectomy, at which time oval cell proliferation was most promi nent. In the developing liver, an elevated level of HGF transcripts wa s found between 4 and 21 days after birth. The expression of c-met als o slightly increased at the same time. In situ hybridization showed th at the transcripts for HGF were localized in desmin-positive Ito cells , whereas the transcripts for c-met were strongly expressed by total c ells. 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 facto rs. The data presented here suggest that HGF is, in combination with o ther growth factors, involved in the proliferation and differentiation of oval cells via a paracrine mechanism.