Med Electron Microsc (1998) 31:53-60 9 The Clinical Electron Microscopy Society of Japan 1998 M. Alison 9 M. Golding 9 V. Emons 9 T.V. Anilkumar C. Sarraf Stem cells of the liver Received: December 10, 1997 / Accepted: January 27, 1998 Abstract Liver regeneration can be accomplished either by the entry of normally proliferatively quiescent, differenti- ated hepatocytes into the cell cycle or, if hepatocyte regen- eration is impaired, by bile ductular cells that migrate centrifugally from the portal tracts before differentiating into hepatocytes. These ductal cells are called oval cells, and their emergence when hepatocyte regeneration is defective has led to the conclusion that they are the progeny of facul- tative stem cells. Oval cells are of great biological interest because they may be the progenitor cells of both hepatocel- lular carcinomas and cholangiocarcinomas; furthermore, they could be useful vehicles for ex vivo gene therapy for the correction of inborn errors of metabolism. Key words Oval cells 9 Liver 9 Bile ducts - Hepatocellular carcinoma 9 Cholangiocarcinoma - Stem cells Liver development The liver primordium consists of endodermal and mesoder- mal components; ventral foregut endoderm gives rise to hepatoblasts, which form the parenchyma (hepatocytes), while both sinusoidal-lining cells and connective tissue com- ponents originate from the mesenchymal tissue, which is invaded by the hepatic cords. 1 The hepatoblasts that sur- round the portal mesenchyme form a double-layered cylin- der of hepatocytes, the "ductal plate," which remodels and migrates into the portal mesenchyme to form the intrahepatic bile ducts. ~'2 Ductal plate cells transiently ex- press both hepatocyte (alpha-fetoprotein [AFP] and albumin) and ductal markers (gamma glutamyl transferase, GGT) and as such can be considered to be oval cell equiva- lents. Indeed, the oval cell response that ultimately gener- ates new hepatocytes is, in effect, a reversal of this develop- mental response. The proliferative organization of the adult liver In continually renewing epithelia (e.g., gut mucosa and epi- dermis), the stem cells represent the progenitors of the migrating and differentiating cells. ~ In the liver, it has been proposed that the hepatic plates represent the trajectory along which cells migrate centrifugally from the periportal areas to the centrilobular regions, where they ultimately die by apoptosis. 4 Following the fate of tritiated thymidine- labeled cells in adult rat liver over a 5-week period, hepato- cytes were thought to have moved a distance of 46~m (-1 cell) from the portal rim toward the hepatic vein. This ob- servation led to the "streaming liver" hypothesis, which has engendered considerable discussion. 5'6 Most significantly, studies utilizing genetic labeling with an Escherichia coli [3- galactosidase gene do not support the streaming liver hy- pothesis. For example, when rat hepatocytes are labeled in vivo at 24h after a two-thirds partial hepatectomy (2/3PH) by an amphotropic retrovirus carrying the [3-galactosidase gene coupled to a nuclear localization signal, then initially most labeled cells are located in the periportal and midzonal regions; however, because the distribution of la- beled cells did not change during the proceeding 15 months, this strongly argued against the streaming liver hypothesis] Thus, it seems likely that in the unperturbed state hepato- cytes do not move in a unidirectional manner, but instead remain fairly static. M. Alison (~) 9 M. Golding. V. Emons 9 T.V. Anilkumar 9 C. Sarraf Histopathology Department, Division of Investigative Science, ICSM at Hammersmith Campus, Du Cane Road, London W12 0NN. UK Tel. +44-181-383-3247; Fax +44-181-740-7417 e-mail: malison@rpms.ac.uk Proliferative responses in the liver The liver is able to mount a prompt proliferative response to parenchymaI loss and other hyperplastic stimuli. These reactions may be categorized as follows: