Reviews and PerspectivesBrief ReviewLinks Between Hepatic Fibrosis, Ductular Reaction, and Progenitor Cell Expansion
Section snippets
Defining HPCs/DRs and the Stem Cell Niche in the Liver
Oval cells, a population of small cells with an ovoid nucleus and a high nuclear-to-cytoplasmic ratio, were initially described in the portal areas of rat livers after chemical injury.5, 6 These cells have been noted to coexpress markers of hepatocytes (albumin) and biliary epithelial cells (keratin-19). Cells with similar but not identical characteristics have also been seen in humans and mice and have been called liver progenitor cells or HPCs. Three-dimensional reconstructions in human liver
HPCs/DRs and Fibrosis
In human liver disease, the DR correlates closely with the severity of fibrosis across a range of liver pathologies, including chronic hepatitis C,49 alcoholic and nonalcoholic steatohepatitis,50, 51 recurrence of viral hepatitis after liver transplantation (where florid DRs with accompanying fibrosis occur in fibrosing cholestatic hepatitis52), and genetic hemochromatosis.53 This has raised the question as to whether the fibrosis is in some way beneficial for HPC-mediated regeneration or
The Extracellular Matrix Components and Their Role in Liver Regeneration
To understand the influence of matrix on HPCs, experiments have targeted specific matrix components.
Future Perspectives
To address the uncertainties in the field, one approach would be to target production of specific matrix components directly. The use of genetic knockout models has been limited due to the critical role of many matrix proteins in embryonic development. However, the development of cell-specific and inducible genetic knockouts such as the Cre-lox75 or FLP-FRT76 systems may allow researchers to address this further. An alternative strategy would be to disrupt cell-matrix signaling specifically in
Conclusions
In HPC-mediated liver regeneration, there are distinct patterns of extracellular matrix remodeling and new matrix deposition involving collagens and laminins. Failure to remodel extracellular matrix impairs the regenerative response. DRs and fibrosis are frequently associated, and HPCs may even contribute to profibrotic signals under some conditions. However, there are models in which collagen and HPCs can show opposing patterns. In contrast, the association between HPCs and laminin appears to
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