Hepatocyte growth factor and c-Met expression in rat and human liver fibrosis.
BACKGROUND
Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes in vitro.


OBJECTIVE
Substitution of HGF was suggested for human liver disease on the basis of animal experiments. The cellular sources of HGF and its receptor, c-Met, in liver disease in vivo are not well defined.


METHODS
We characterised HGF and c-Met expression in normal and cirrhotic human livers and rat livers at various time points after CCl4 administration by in situ hybridisation and immunohistology. HGF transcripts were restricted to resting and activated stellate cells in rat and human liver.


RESULTS
In rat liver, HGF showed peak levels 6-12 h following acute intoxication, and remained increased after repeated CCl4 injury. HGF transcript levels were very low in normal human liver, but excessively raised in fibrosis/cirrhosis. In contrast, HGF immunoreactivity was found not only in perisinusoidal/periductular cells but also in cholangiocytes of proliferating ductules. c-Met RNA and protein was expressed in hepatocytes, cholangiocytes, and arteriolar endothelial cells.


CONCLUSIONS
The HGF-specific immunostaining of proliferating cholangioles in the absence of HGF RNA suggests c-Met-mediated uptake of HGF and paracrine stimulation of cholangiocellular proliferation. Mitogenic effects of HGF on hepatocytes may therefore be accompanied by undesired cholangiogenesis and angiogenesis limiting its therapeutic value in chronic liver disease.
Cramer
Thorsten
T
Institute of Pathology, University of Muenster, Germany.
Schuppan
Detlef
D
Bauer
Michael
M
Pfander
David
D
Neuhaus
Peter
P
Herbst
Hermann
H
D000818:Animals; D002251:Carbon Tetrachloride; D005260:Female; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008099:Liver / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D019899:Paracrine Communication; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride; D019859:Proto-Oncogene Proteins c-met