leave G0mulus, the normally quiescent hepatocytes leave G0 to enter the cell cycle under the influence of many growth factors. Hepatocyte proliferation begins in the periportal re gion of the liver and spreads to the centrilobular re gion. This regenerative response requires each hepatocyte to undergo only 2 rounds of replication to restore normal liver size. Hepatocytes are AZ 3146 capable of large scale clonal expansion within a diseased liver. Following very extensive liver damage or in situations in which hepatocyte regeneration after damage is compromised, a potential stem cell component locat ed within the smallest branches of the intrahepatic biliary tree is activated. Hepatic progenitor cells amplify a biliary population of transit ampli fying cells that are bipotential, capable of differenti ating into either hepatocytes or cholangiocytes.
These cells have been observed after severe hepatocellular necrosis, chronic viral hepatitis, alcoholic liver dis ease, and nonalcoholic fatty liver disease. It is thought that the activation of a potential stem cell compart ment BIX 02189 leads to the formation of reactive ductules, anastomosing cords of immature biliary cells with an oval nucleus and small rim of cytoplasm. Differentia tion toward the hepatocyte lineage occurs via inter mediate hepatocytes, polygonal cells with a size and phenotype intermediate between progenitor cells and hepatocytes. Intermediate hepatocytes become more numerous with time and extend further into the liver lobules. This sequence of changes suggests gradual differentiation of human progenitor cells into inter mediate hepatocytes.
The Hepatocyte proliferation rate increases in chronic hepatitis with increased histological appear ance of cellular damages until cirrhosis is reached, at which point the proliferation rate falls. This fall probably reflects replicative senescence, although the diversion of blood flow through the liver probably plays a part. The reduction in hepatocyte prolif eration indices in chronic hepatitis occurs concur rently with the activation of HPCs. The de velopment of an oval cell reaction in response to hepatocyte replicative senescence has been demon strated in a transgenic mouse model of fatty liver and DNA damage. In this model, mice developed fatty livers and large number of senescent hepato cytes. A striking oval cell response related to the number of senescent mature hepatocytes.
The hepatocytes generated from oval cells in severe ly damaged cirrhotic livers may have a high risk for neoplastic transformation. Stem cells in the liver are proposed to be from two origins: endogenous or intrahepatic and exoge nous or extrahepatic. Included in the intrahepatic stem cell compartment are the HPCs which are greater in number but with short term proliferative capacity. HPCs are thought to be localized within the canals of Hering, interlobular bile ducts. In cluded in the extrahepatic stem cell compartment are cells derived from bone marrow and peripheral blood cells, thes