Regeneration of the Liver

The liver has a remarkable capacity to regenerate after injury and to adjust its size to match its host. Within a week after partial hepatectomy, which, in typical experimental settings entails surgical removal of two-thirds of the liver, hepatic mass is back essentially to what it was prior to surgery. Some additional interesting observations include:

• In the few cases where baboon livers have been transplanted into people, they quickly grow to the size of a human liver.
• When the liver from a large dog is transplanted into a small dog, it loses mass until it reaches the size appropriate for a small dog.
• Hepatocytes or fragments of liver transplanted in extrahepatic locations remain quiescent but begin to proliferate after partial hepatectomy of the host.

These types of observations have prompted considerable research into the mechanisms responsible for hepatic regeneration, because understanding the processes involved will likely assist in treatment of a variety of serious liver diseases and may have important implications for certain types of gene therapy. A majority of this research has been conducted using rats and utilized the model of partial hepatectomy, but a substantial body of confirmatory evidence has accumulated from human subjects.

The Dynamics of Liver Regeneration

Partial hepatectomy leads to proliferation of all populations of cells within the liver, including hepatocytes, biliary epithelial cells and endothelial cells. DNA synthesis is initiated in these cells within 10 to 12 hours after surgery and essentially ceases in about 3 days. Cellular proliferation begins in the periportal region (i.e. around the portal triads) and proceeds toward the centers of lobules. Proliferating hepatocytes initially form clumps, and clumps are soon transformed into classical plates. Similarly, proliferating endothelial cells develop into the type of fenestrated cells typical of those seen in sinusoids.

It appears that hepatocytes have a practically unlimited capacity for proliferation, with full regeneration observed after as many as 12 sequential partial hepatectomies. Clearly the hepatocyte is not a terminally differentiated cell.

Changes in gene expression associated with regeneration are observed within minutes of hepatic resection. An array of transcription factors (NF-kB, STAT3, fos and jun) are rapidly induced and probably participate in orchestrating expression of a group of hepatic mitogens. Proliferating hepatocytes appear to at least partially revert to a fetal phenotype and express markers such as alpha-fetoprotein. Despite what appears to be a massive commitment to proliferation, the regenerating hepatocytes continue to conduct their normal metabolic duties for the host such as support of glucose metabolism.

Stimuli of Hepatic Regeneration

Hepatic regeneration is triggered by the appearance of circulating mitogenic factors. This conclusion was originally supported by experiments demonstrating that quiescent fragments of liver that had been transplanted to extrahepatic sites would begin to proliferate soon after partial hepatectomy, and also that hepatectomy in one of a pair of parabiotic rats led to hepatic proliferation in the other of the pair.

As might be expected, liver regeneration seems to be supported by a group of mitogens and growth factors acting in concert on several cell types. Some of the major and well-studied players that act together in this process include:

• Hepatocyte growth factor (scatter factor) levels rise to high levels soon after partial hepatectomy. This is the only factor tested that acts by itself as a potent mitogen for isolated hepatocytes cultured in vitro. This factor is also of critical importance in development of the liver, as target deletions of its gene lead to fetal death due to hepatic insufficiency.
• TNF-alpha, which stimulates proliferation of hepatic endothelial cells.
• Interleukin-6, which acts as a biliary epithelial mitogen.
• Epidermal growth factor.
• Norepinephrine potentiates the mitogenic activity of EGF and HGF.
• Insulin is required for regeneration but appears to play a permissive rather than mitogenic role.

The processes and signals involved in shutting down the regenerative response are less well studied than those that stimulate it. TGF-beta1, which is known to inhibit proliferative responses in hepatocytes, is one cytokine involved in this process, but undoubtedly several others participate.

References and Reviews

• Michalopoulos GK, DeFrances MC: Liver regeneration. Science 276:60, 1997.