Liver regeneration under normal circumstances proceeds through proliferation of all cellular elements of the liver. Studies with rodent models have shown that when proliferation of hepatocytes is inhibited, progenitor cells arising from the biliary compartment transdifferentiate into "oval/progenitor" cells, which proceed to differentiate into hepatocytes. Recent studies have shown that the same pathways may operate in human liver failure. The growth factor receptors (HGF [hepatocyte growth factor] receptor) and epidermal growth factor receptor are key mitogenic receptors for both hepatocytes and progenitor cells. Our current study used the biliary and progenitor marker EpCAM (epithelial cell adhesion molecule) to detect "regenerative clusters" of mixed cholangiocyte-hepatocyte differentiation. We determined that expression of metabolic equivalent and epidermal growth factor receptor occurs in biliary cells, progenitor cells, and hepatocytes, whereas activation of metabolic equivalent and epidermal growth factor receptor is limited to regenerative cluster hepatocytes. These histologic events are associated with expression of apoptosis-inducing FAS and mitoinhibitory protein glypican 3. Cell proliferation was overall suppressed in regenerative clusters. Transdifferentiation of biliary and progenitor cells appears to be regulated by a complex interaction of signals promoting and arresting growth.
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