Hepatocyte growth factor in transgenic mice: effects on hepatocyte growth, liver regeneration and gene expression

Attention has recently been focused on hepatocyte growth factor as a major candidate factor in liver regeneration because it is the most potent known mitogen for hepatocytes in vitro. However, hepatocyte growth factor also displays diverse activities in vitro as scatter factor, as an epithelial morphogen, as a pluripotent mitogen and as a growth inhibitor. Consequently, we developed transgenic mice that expressed hepatocyte growth factor under the control of albumin regulatory sequences to examine its in vivo role in hepatocyte growth. Hepatocytes of these mice expressed increased levels of hepatocyte growth factor as an autocrine growth factor. Hepatocyte growth factor was a potent stimulus for liver repair; the livers of hepatocyte growth factor-transgenic mice recovered completely in half the time needed for their normal siblings after partial hepatectomy. This transgenic model also enabled us to study the chronic effects of hepatocyte growth factor expression. During several months of observation, the labeling index of hepatocytes in albumin-hepatocyte growth factor mice was doubled, and liver DNA content was increased compared with that in wild-type mice. To identify intermediate signaling pathways for hepatocyte growth factor that might regulate this increased growth response, we examined transgenic mice for changes in expression of genes that are known to be regulated during liver regeneration. We found that levels of c-myc and c-jun mRNA were increased in the hepatocyte growth factor-transgenic mice. In additional experiments the increased c-myc expression was the consequence of increased transcription rates as seen in nuclear run-on and myc-CAT reporter gene experiments. We conclude that hepatocyte growth factor increases growth and repair processes when expressed for long periods in the liver and that c-myc and c-jun may be important intermediaries in the hepatocyte growth response caused by hepatocyte growth factor.