Abstract
Hepatocyte growth factor (HGF) has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ERT transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70–80%) of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH), which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4)-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth.
Highlights
The partial hepatectomy (PH) model, in which two-thirds of the rat or mouse liver is removed and the remaining lobes enlarge to restore the original liver mass, is an ideal environment to study organ regeneration and controlled growth after injury [1,2]
hepatocyte growth factor (HGF) is a pleiotropic growth factor that has been shown to be essential for liver regeneration because it serves as the main mitogenic stimulus driving hepatocytes toward proliferation [1,2]
Despite Genetic Recombination, Unrecombined HGF mRNA and Protein are Present in the Livers of HGFex.5 flox; Cre+/2 Mice
Summary
The partial hepatectomy (PH) model, in which two-thirds of the rat or mouse liver is removed and the remaining lobes enlarge to restore the original liver mass, is an ideal environment to study organ regeneration and controlled growth after injury [1,2]. The hallmark of liver regeneration is proliferation of adult hepatic cell types, including hepatocytes, biliary epithelial cells, endothelial cells, and hepatic stellate cells (HSCs) [1]. Cell proliferation and regeneration is tightly regulated by a series of cell signaling pathways and cascades that are activated immediately after resection. One of these is the hepatocyte growth factor (HGF)/ Met pathway. HGF is a pleiotropic growth factor that has been shown to be essential for liver regeneration because it serves as the main mitogenic stimulus driving hepatocytes toward proliferation [1,2]. HGF activation and utilization are crucial events for liver regeneration and provide an early and sustained signal for hepatocyte proliferation [10]
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