Hepatic "stem" cells: coming full circle

Activation, proliferation, and differentiation of a distinct phenotype of cells, called oval cells, are observed after severe hepatic injuries in which the proliferation of existing hepatocytes is inhibited. Under those conditions, oval cells can act as bipotential progenitors of the two types of epithelial cells within the liver, hepatocytes and bile ductular cells. Oval cells are also believed to play a role in the hepatocellular carcinoma and cholangiocarcinoma development; although circumstantial data are available, no direct evidence exists to support this theory. Oval cells have usually been thought to be the progeny of an hepatic stem cell, native to the liver. Recently, however, we, as well as others, have obtained clear evidence that in the rodents, hepatic oval cells, or at least a fraction of them, can derive from a precursor cell of bone marrow origin. The rodent data have been supported by recent findings that human bone marrow cells are capable of becoming hepatocytes and cholangiocytes as well. Having shown that oval cells can be derived from an extrahepatic source, we now have the technology to address many unanswered questions in oval cell origin, fate, and physiology through the use of sex-mismatched bone marrow transplants.