Hepatocyte Growth Factor mRNA in Human Liver Cirrhosis as Evidenced by in situ Hybridization

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Abstract
Background: Hepatocyte growth factor (HGF) is a strong mitogen of hepatocytes, and HGF-producing cells have been reported to be Ito cells or endothelial cells in the sinusoid of the liver. No reports have been published about the localization of HGF mRNA in human liver cirrhosis. Methods: In situ hybridization (ISH) for HGF mRNA was performed in 5 normal liver and 16 human liver cirrhosis specimens, using 1 RNA probe and 3 oligonucleotide probes labeled with 35S. Results: A positive signal was obtained in 15 of these cases. In five normal liver specimens, signals of HGF mRNA were not obtainable. In 13 of the 15 cases of liver cirrhosis, HGF mRNA was present in the periphery of the regenerative nodules. This peripheral pattern was seen in regenerative nodules with irregular nodule to septal interfaces. Combined immunohistochemistry and ISH showed that vimentin and CD 68-positive cells consistent with macrophages expressed HGF mRNA in such cases. In three specimens with diffuse signal for HGF mRNA in the hepatic nodules, signals localized to the sinusoidal spaces. HGF mRNA-positive cells were spindled and polygonal in shape, suggesting endothelial, Kupffer, and/or Ito cells of origin. In the diffuse pattern the peripheral margins of the regenerative nodules appeared well-defined. In one case regenerative nodules with both diffuse and peripheral signal patterns were present in the same section. There was no relationship among HGF mRNA, etiology, and macroscopic appearance of liver cirrhosis. Conclusions: HGF gene transcription in human liver cirrhosis nodules may be heterogeneous, probably related to the degree of activity of the regenerative nodules. HGF appears to be produced by the mesenchymal cells, including Ito cells, macrophages (Kupffer cells), and endothelial cells in human liver cirrhosis.