The stem cells of the liver ? a selective review

Abstract

The current status of the much-debated question of the still-hypothetical stem cells of the liver is reviewed, with an emphasis on their role in hepatocarcinogenesis. The widely held view of the primacy of the hepatocyte, notably of the mononuclear diploid type, in this process--the "hepatocytic theory"--has been compared with variants of the "stem cell hypothesis" based on the "non-parenchymal epithelial cells" of the liver--the "oval" or biliary ductular cells, the "nondescript periductular" cells and the "primitive" bipotential epithelial cells. An attempt has been made to concentrate mainly on the more recent publications, in an effort to balance the conflicting opinions expressed by comparing results obtained by the newer procedures currently in use. Despite some interesting and relevant findings it appears that the evidence in favour of the stem-cell hypothesis is still circumstantial and that the hepatocytic theory has not been invalidated. Presumably the question of the hepatic stem cells will be answered when the riddle of hepatocarcinogenesis has been solved.

Heterogeneity and plasticity of hepatocyte lineage cells

“…For this reason, after BMTx, hepatocytes of donor origin appear after relatively long periods of time. Thus, continued exploration of experimental models of liver injury and chemical hepatocarcinogenesis over the last 30 years (for evolution of these concepts, see Sell,44,79,94,142 Farber,74,75 Alterman, 76 Dunsford, 84 and Alison, 87 ) have resulted in the hypothesis that different insults may call forth a response of different cells in the hepatic lineage (heterogeneity), and that these cells may have different potential to form cells of other types (plasticity) after liver injury or to serve as the cellular origin of HCCs in response to chemical hepatocarcinogens. FIG.…”

“…After allyl alcohol treatment, the necrotic periportal zone is restored by proliferation of periductular liver stem cells that differentiate as they expand across the necrotic periportal area. 76 ). The conclusion that these nodules were precursors to cancer implied that HCC arose from mature hepatocytes that were initiated by the carcinogen and then stimulated to proliferate.…”

“…79,80 We postulated that nodules represented protected environments in which oval cells could thrive. 79 From such models, different groups have concluded that HCC arises from hepatic foci that form nodules, 48,[73][74][75][76][77][78]82 from LPCs located in the terminal ducts, 58,59,81,83,[85][86][87]90,95,96 or from periductular LPCs. 36,37,44,79,84 For example, using a modified Solt-Farber model, Alison et al described both ductal proliferation 83,96 and nonductal columns of oval cells within the sinusoids or single cells insinuated within existing plates.…”

Bile Ductule Formation in Fetal, Neonatal, and Infant Livers Compared With Extrahepatic Biliary Atresia

“…More recently, in the amount of PCNA staining of hepatocytes between in-the possibility that a stem cell compartment (oval cells) exists fants without primary liver disease (control) and the biliary in the liver has been strongly advocated. 52,55,59,60 However, atresia cases. However, in the case of bile ductular cells, we oval cells in experimental models invade the liver sinusoids did observe a statistical difference between control and bili-along the space of Disse, 50 rather than form ductules that widen the periportal parenchyma, as seen in biliary atresia.…”

The tetratricopeptide repeat containing Tg737 gene is a liver neoplasia tumor suppressor gene

“…In these systems, reestablishment of di erentiation control by replacement of the defective gene results in external di erentiation signal-sensitive terminal differentiation of the neoplastic cell (Hennings et al, 1993;Sawyers et al, 1991;Sell and Pierce, 1994). In the liver, the stem cells which gives rise to partially and completely di erentiated epithelial cells, including hepatocytes and ductal epithelial, are known as oval cells (Aterman, 1992;Brill et al, 1993;Coleman et al, 1993;Fausto, 1990;Marceau et al, 1989;Sell, 1993;Thorgeirsson, 1993). Oval cells are hypothesized to be the cell type which undergoes neoplastic transformation and which gives rise to multiple liver tumor types including hepatocellular carcinomas, ductal carcinomas and undi erentiated carcinomas (Aterman, 1992;Brill et al, 1993;Coleman et al, 1993;Factor et al, 1994;Fausto, 1990;Marceau et al, 1989;Sell, 1993;Thorgeirsson, 1993).…”