56,76 This was followed by a flurry of reports on the ability of transplanted bone

marrow or cord blood progenitors to repopulate animal models of liver injury.77–80 The most notable of these used the mouse model of tyrosinemia,79 and demonstrated that the liver could be completely regenerated by bone marrow stem cells. This phenomenon was subsequently found to be predominantly due to fusion.81 While there continues to be controversy regarding whether bone marrow cells can transdifferentiate into hepatocyte-like cells under certain conditions,82 the weight of evidence suggests that the contribution of bone marrow to normal liver regeneration is insignificant.83,84 The observation that liver progenitor cells have mixed GSK2126458 epithelial and mesenchymal markers72,73,85 and the ease by which mesenchymal stem cells can be converted to hepatocyte-like cells86–88 raised the possibility that they may arise from the mesenchymal

lineage via mesenchymal to epithelial transition. Sicklick et al.89 further proposed that progenitor cells may be derived from hepatic stellate cells, and that the sonic hedgehog pathway regulated this process. In a follow up study, Yang et al.90 used cell fate mapping to show that stellate cells could became oval cells when activated Ibrutinib in liver injury, and that these cells participate in ductular proliferation. The notion that there is a common schema within the stellate cell driving both fibrosis and regeneration by fluxing between epithelial medchemexpress and mesenchymal phenotypes91,92 is an attractive one, but has not been borne out by other investigations. Careful fate mapping studies failed to show any evidence of mesenchymal to epithelial transition or vice versa during liver injury.93,94 In light of conflicting evidence, the role of epithelial-mesenchymal transition and vice versa in liver injury and repair remains highly controversial.95,96 Nevertheless, taken in context with current evidence,

it is likely that the majority of liver progenitor cells are in situ cells that are descendants of the fetal ductal plate.75 The main strategy in attempting to augment regeneration in the clinical setting thus lies in increasing the numbers of these progenitor cells following liver injury, either by stimulating the stem cell niche to proliferate, or simply by transplanting more progenitor cells into the injured liver. The role of progenitor cell regeneration in normal liver physiology is still debated. These cells likely have no significant role in day-to-day liver turnover.97 The progenitor compartment is activated only in severe liver injury, and the belief that it plays an important role in regenerating the injured liver comes from three lines of evidence.