Liver regeneration: alternative epithelial pathways

Abstract

Loss of hepatic tissue triggers a regenerative response in the whole organ. Under typical normal conditions, all hepatic cells (epithelial: hepatocytes and biliary epithelial cells; non-epithelial: stellate cells, macrophages and endothelial cells) undergo one to three rounds of replication to establish the original number of cells and restore organ size. The review summarizes the literature of regenerative patterns in situations in which proliferation of either hepatocytes or biliary epithelial cells is inhibited. The evidence strongly suggests that under these circumstances, hepatocytes or biliary epithelial cells can function as facultative stem cells for each other and replenish the inhibited cellular compartment by a process of transdifferentiation, involving complex signaling pathways. These pathways are activated under experimental conditions in rodents and in fulminant hepatitis associated with liver failure in humans. Mechanistic analysis of these pathways has implications for liver biology and for potential therapeutic modalities in human liver disease.

Figure 1

In standard liver regeneration, as after 2/3 partial hepatectomy, all cells are capable of proliferation. Hepatocytes give rise to hepatocytes and biliary cells generate biliary cells. When hepatocyte proliferation is blocked, biliary cells replicate themselves and they also expand into a large number of oval cells, with gene expression patterns of both biliary and hepatocyte specificity. Sources of oval cells are portal ductules and biliary cells of the canals of Hering. The oval cells transition into a hepatocyte phenotype and rescue the hepatocyte compartment.