Hepatic progenitor cells, stem cells, and AFP expression in models of liver injury

Abstract

Adult hepatocytes and liver-cell progenitors play a role in restoring liver tissue after injury. For the study of progenitor cells in liver repair, experimental models included (a) surgical removal of liver tissue by partial hepatectomy; (b) acute injury by carbontetrachloride; (c) acute injury by d-galactosamine (GalN) and N-nitrosomorpholine (NNM); and (d) chemical hepatocarcinogenesis by feeding NNM in low and high doses. Serological and immunohistological detection of alpha-fetoprotein gene expression served to follow pathways of cellular differentiation. Stem cells were not required in models of surgical removal of parenchyma and in carbon tetrachloride intoxication of adult hepatocytes. In contrast, regeneration of liver occurred through biliary epithelial cells in injuries induced by GalN and NNM. These biliary epithelial cells, collectively called oval cells, are most probably derived from the canals of Hering. Proliferating bile duct cells reached a level of differentiation with reactivation of foetal genes and significant alpha-1-fetoprotein (AFP) synthesis signalling a certain degree of retrodifferentiation with potential stemness. Due to the same embryonic origin of bile ducts and hepatocytes, biliary epithelium and its proliferating progeny (oval cells) have a defined role in liver regeneration as a transit and amplification compartment. In their early proliferation stage, oval cells were heavily engaged in DNA synthesis ([3H]thymidine labelling). Pulse-chase experiments during experimental hepatocarcinogenesis exhibited their development into hepatocytes with high risk for transformation and leading to foci of altered hepatocytes. Hepatocellular carcinomas may arise either from proliferating/differentiating oval cells or from adult hepatocytes; both cell types have stem-like properties. AFP-positive and AFP-negative carcinomas occurred in the same liver. They may represent random clonal origin. The heterogeneity of phenotypic marker (AFP) correlated with a process of retrodifferentiation.

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

“…Alpha‐fetoprotein (AFP) is not only a representative tumor marker of hepatocellular carcinoma but is also known as a marker of HPC induction in both clinical4 and experimental8, 9 settings. AFP is produced by bipotent HPCs and yolk sac endoderm, and serum AFP concentrations are increased during embryonic development.…”

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…6,7 These findings support the concept that the ductular reaction represents an expansion of the progeny of typically inconspicuous liver progenitors that reside along Canals of Hering in healthy adult livers and suggest that the ductular reaction is involved in liver repair. 8 Fortunately, knowledge about the mechanisms that regulate the ductular response to liver injury is growing [9][10][11][12][13] because such information might suggest novel therapeutic targets to reduce fibrosis and improve regeneration in individuals with alcoholinduced liver injury.…”

Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice

“…2 Some progenitors are bi-potent, that is capable of differentiating along either epithelial lineage, while others are committed to a specific fate. 5,6 Less certain is whether adult livers also retain more primitive multipotent progenitors, similar to mesendodermal cells that give rise to hematopoietic, endothelial, adipocytic, smooth muscle-like, and epithelial cell types during embryogenesis. 7,8 Development of many tissues, including the liver, requires migration of the mesendoderm during gastrulation.…”