indicating that fields of EpCAM-positive hepatocytes are progeny of EpCAM-positive DRs suggest that mutational events may arise in the DR ecotones, paralleling species evolution geographically. Some may be evolutionarily adaptive at the cell population level. For example, mutations in rapidly proliferative and therefore mutationally susceptible hepatobiliary progenitors might lead to emergence of hepatocytes resistant to disease (e.g., resistant to copper accumulation in Wilson’s disease or to lipotoxicity in fatty liver disease). Of course, it also opens the door to deeper, more complex understandings of hepatocarcinogenesis associated with Dorsomorphin chemical structure emergence of DRs. The prevailing concept of liver regeneration is that replenishment of cellular loss is by proliferation of mature cells and that activation of the stem/progenitor cell compartment(s) occur(s) when the proliferative capacity of mature cells is exhausted or MI-503 clinical trial inhibited. The absence of DRs in normal livers supports this. However, a basal activity of the stem cell niche to generate hepatocytes as a regular process of cellular renewal is not excluded, particularly
given the discovery of clonal patches of CoH-derived hepatocytes.30 This maintenance activity does not occur through overt DR, but possibly through “post-natal hepatoblasts” and “peribiliary hepatocytes.”7,23,31 The relative dynamics and contributions of hepatocyte replication versus DRs to parenchymal restitution in chronic liver disease appears to change with time, with increasing proliferation of DR hepatobiliary cells correlating with diminishing hepatocyte replicative
potential and increasing senescence.4,16,18 A recent study of hepatic progenitor cells in HCV found a significant selleck correlation between DRs and older age, which supports the role of senescence.46 That DRs are a source of hepatocellular restoration is most strongly supported by recent studies showing that EpCAM-positive hepatocytes had telomere lengths longer than those of EpCAM-negative hepatocytes (which presumably are older and/or derive from replication of earlier hepatocytes), but slightly shorter than those of the DR cells, which express telomerase.6 Thus, in diseases of all kinds, DRs mediate repair, at least in part, and may reflect activation of multiple stem/progenitor niches. From a tissue biological point of view, the basis of DR success as a prevalent reparative mechanism lies in the “geographic” uniqueness of the niche from which DR arises, the portal–parenchymal interface. Here, interactions between the hepatobiliary cells with portal and periportal mesenchymal cells are likely through both production of diffusible growth controlling factors and physical cell–cell contact. For example, hepatocyte:sinusoidal endothelium contact is instrumental in regeneration.