WOUND-HEALING IN THE LIVER WITH PARTICULAR REFERENCE TO STEM-CELLS

The efficiency of liver regeneration in response to the loss of hepato cytes is widely acknowledged, and this is usually accomplished by the triggering of normally proliferatively quiescent hepatocytes into the cell cycle. However, when regeneration is defective, tortuous ductular structures, initially continuous with the biliary tree, proliferate a nd migrate into the surrounding hepatocyte parenchyma. In humans, thes e biliary cells have variously been referred to as ductular structures , neoductules and neocholangioles, and have been observed in many form s of chronic liver disease, including cancer. In experimental animals, similar ductal cells are usually called oval cells, and their associa tion with impaired regeneration has led to the conclusion that they ar e the progeny of facultative stem cells. Oval cells are of considerabl e biological interest as they may represent a target population for he patic carcinogens, and they may also be useful vehicles for ex vivo ge ne therapy for the correction of inborn errors of metabolism. This rev iew proposes that the liver harbours stem cells that are located in th e biliary epithelium, that oval cells are the progeny of these stern c ells, and that these cells can undergo massive expansion in their numb ers before differentiating into hepatocytes. This is a conditional pro cess that only occurs when the regenerative capacity of hepatocytes is overwhelmed, and thus, unlike the intestinal epithelium, the liver is not behaving as a classical, continually renewing, stem cell-fed line age. We focus on the biliary network, not merely as a conduit for bile , but also as a cell compartment with the ability to proliferate under appropriate conditions and give rise to fully differentiated hepatocy tes and other cell types.