Advances in liver regeneration

Abstract

Liver regeneration after partial hepatectomy is the only example of a regenerative process in mammals in which the organ/body weight ratio returns to 100% of the original when the process is complete. The adjustment of liver weight to the needs of the body suggests a complicated set of control points, a ‘hepatostat’. There has been much progress in elucidation of mechanisms involved in initiation of liver regeneration. More recent studies have focused on termination pathways, because these may be the underlying controls of the hepatostat and their elimination may be relevant to hepatic neoplasia. When the standard regenerative process is thwarted due to failure of either hepatocytes or biliary epithelial cells to proliferate, each of the two epithelial compartments can function as a source of facultative stem cells for the other.

Keywords::

• EGFR
• extracellular matrix
• facultative stem cell
• HGF
• integrin linked kinase
• liver regeneration

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Regeneration of liver after partial hepatectomy results in complete restoration of its mass to the original 100% of the organ size.

• Initiation of liver regeneration occurs by a combination of signaling pathways involving mitogenic growth factors (HGF, EGF) and several nonmitogenic cytokines (IL6, TNF, bile acids, etc.). There is not a single one of these that either triggers liver regeneration by itself or whose elimination abolishes liver regeneration.

• Termination of liver regeneration is mediated by multiple complex processes involving TGF-β1, extracellular matrix and integrins and GPC3/CD81 signaling pathways. These pathways are also important in the context of genomic abnormalities seen in hepatocellular carcinoma.

• When either hepatocytes or biliary epithelial cells are unable to repair damage to their compartment, either one can function as facultative stem cell for the other to promote effective regeneration.

• The ability of hepatocytes and biliary epithelial cells to function as facultative stems for each other appears to operate in humans during fulminant hepatic failure.