Zonal regulation of gene expression during liver regeneration of urokinasetransgenic mice

'Liver gene transcription plays a fundamental role in the hepatic reparativ e response to injury. However, little is known about the functional relatio nship of gene expression between diseased and regenerative compartments fol lowing a liver injury. To address the hypothesis that the control of gene e xpression and the cellular proliferative response are specific to diseased and regenerative liver compartments independently, we assessed the expressi on of liver growth modulators, hepatocyte proliferation, and apoptosis in t ransgenic livers overexpressing the urokinase-type plasminogen activator (u PA). uPA livers have regenerative nodules that are visually distinct from t he surrounding diseased compartments. Northern analyses using RNA from micr odissected regenerative and diseased compartments showed that, among the kn own liver growth factors studied, there was a selective increase in the exp ression of hepatocyte growth factor (HGF) in diseased compartments above th e levels seen in regenerative compartments and in livers of nontransgenic l ittermates, Despite the high level of HGF mRNA in diseased compartments, he patocyte proliferation was low In contrast, in regenerative compartments, w here HGF mRNA was low hepatocyte proliferation was abundant. For growth inh ibitors, mRNA expression for transforming growth factor beta(1) (TGF-beta(1 )), p53, and activin A was increased in diseased compartments, where hepato cytes displayed apoptosis. These findings define a zone-specific regulation of gene expression in injured livers and point to an important role of the diseased microenvironment in the fate of hepatocytes during the regenerati ve process.