Gastroenterology

Gastroenterology

Volume 146, Issue 2, February 2014, Pages 349-356
Gastroenterology

Reviews and Perspectives
Brief Review
Links Between Hepatic Fibrosis, Ductular Reaction, and Progenitor Cell Expansion

https://doi.org/10.1053/j.gastro.2013.11.034Get rights and content

Interactions between cells and their extracellular matrix have been shown to be crucial in a wide range of biological processes, including the proliferation and differentiation of stem cells. Ductular reactions containing both hepatic progenitor cells and extracellular matrix are seen in response to acute severe and chronic liver injury. Understanding the molecular mechanisms whereby cell-matrix interactions regulate liver regeneration may allow novel strategies to enhance this process. Both the ductular reaction in humans and hepatic progenitor cells in rodent models are closely associated with collagen and laminin, although there is still debate about cause and effect. Recent studies have shown a requirement for matrix remodeling by matrix metalloproteinases for the proliferation of hepatic progenitor cells and suggested defined roles for specific matrix components. Understanding the interactions between progenitor cells and matrix is critical for the development of novel regenerative and antifibrotic therapies.

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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    Conflicts of interest The authors disclose no conflicts.

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