Zongyi Hu

Hepatic Stem Cell Compartment: Activation and Lineage Commitment

There is increasingly robust experimental evidence in support of the presence of a pluripotent cell compartment in the liver 1 , 2 , 3 , 4 , 5 , 6 , 7 . This compartment can under certain conditions function as a stem cell compartment and provide the needed progeny for regeneration of the hepatic parenchyma 8 , 9 . In the adult rat, specific conditions can be utilized to induce proliferation of a distinct population of small epithelial cells in the ductal structures of the liver 10 , 11 . These cells, conventionally described as oval cells, are characterized by ovoid nuclei and basophilic cytoplasma 10 , and display features of both bile duct cells and fetal hepatocytes 11 , 12 , 13 . There are three experimental systems, two in the rat and one in the mouse, in which it has been conclusively demonstrated that oval cells are capable of differentiation into hepatocytes 8 , 11 , 14 . The developmental potential of oval cells is, however, not restricted to hepatic lineages. Oval cells can differentiate into intestinal-type epithelia, and have been implicated in the development of pancreatic tissues 8 , 11 , 15 , 16 , 17 ; Fig. 1). The observations that sub-populations of proliferating oval cells phenotypically similar to early hepatoblasts, and that oval cells originate in or around the ductular structures in the portal area, strongly support the notion that the hepatic stem cell compartment resides in these structures 2 , 7 , 9 . Furthermore, present evidence clearly indicates that the hepatic stem cell compartment functions as a facultative stem cell compartment that is activated when the parenchymal cells are unable to proliferate in response to growth stimuli 2 , 8 , 18 , 19 .

Cellular Biology of the Rat Hepatic Stem Cell Compartment

The existence of hepatic stem cells has been, and no doubt will continue to be, a matter of considerable controversy. This controversy is partly fueled by the fact that cell turnover in the liver is very slow and the two major types of hepatic epithelial cells, hepatocytes and biliary epithelia, are capable of proliferation and can, at least in a healthy liver, meet replacement demands of cellular loss from these two differentiated populations. The best example of the capacity of adult hepatocytes and bile epithelial cells to proliferate is seen after partial hepatectomy in rats and mice, in which the compensatory hyperplasia of these cells in the remaining lobes restore the liver mass. The increased use and success of liver transplantation in clinical medicine have shown that these animal models correctly reflect the capacity of the human liver to regenerate (Van Thiel et al., 1989). What then is the evidence that there exists a stem cell compartment in the liver? The existence of hepatic stem cells was first postulated by Wilson and Leduc in 1958 based on experiments involving liver regeneration in the mouse after chronic injury induced with a methionine-rich basal diet mixed with an equal amount of bentonite (Wilson and Leduc, 1958). The authors concluded that “prolonged and severe injury to the liver may make direct restoration by division of pre-existing parenchymal cells impossible, and that, when this occurs, the new parenchyma is derived from the indifferent cholangiole cells.”