Liver regeneration following hepatic injury

Abstract

While the process of liver regeneration has been the subject of a multitude of investigations, the overwhelming majority of these studies have examined hepatocellular proliferation in the in vivo model of partial hepatectomy. In contrast, the characteristics and mechanisms of hepatic regeneration stimulated by liver cell loss from hepatocyte injury and cell death rather than surgical resection are largely unknown. The reasons for this imbalance in our knowledge of liver regeneration are probably twofold. The first is that many of the studies on hepatic regeneration have been fueled by an interest in general cellular mechanisms of proliferation and not a desire to understand liver cell-specific responses to a regenerative stimulus. Investigations into the process of cellular proliferation have centered on the liver because partial hepatectomy represents a unique in vivo whole-organ model in which a quiescent cell population is simultaneously stimulated to enter the cell cycle. Thus, a great deal of information has been generated about liver regeneration after partial hepatectomy because of the strength of the model rather than an interest in specific hepatic events. Secondly, there is an inherent experimental difficulty in any study of regeneration after hepatic injury that is not present in the partial hepatectomy model. In injury models, the two processes of injury/death and regeneration are intertwined, which greatly complicates any study of regeneration. For instance, the cytokine tumor necrosis factor-α (TNFα) has been found to promote DNA synthesis after partial hepatectomy (Akerman et al., 1992). During toxic liver injury, TNFa is expressed (Czaja et al., 1989a) and contributes to hepatocyte injury and cell death (Czaja, Xu and Alt, 1995). It is difficult to determine the direct effects of TNFa on the process of post-injury regeneration by experimentally blocking the biological activity of TNFα, because such efforts will also decrease the amount of liver cell death and therefore reduce the stimulus for liver regeneration. Any evidence of a TNFα mitogenic effect may be lost in the background of a marked decrease in liver regeneration due to reduced liver cell death. The use of the partial hepatectomy model, in which the quantity of hepatocyte proliferation relies only on the extent of surgical removal of liver tissue (Bucher and Swaffield, 1964), obviates such problems.