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 dominant processes leading to regeneration of the liver following removal of tissue (partial hepatectomy) are compensatory hypertrophy (enlargement of hepatocytes) followed by hyperplasia (proliferation of hepatocytes). Proliferating hepatocytes also are capable of transdifferentiating into other cell types such those of the biliary system. Blood borne stem cells from bone marrow can participate in regeneration but are thought to play a minor role, except perhaps when hepatocytes are greatly compromised by toxic injury.

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 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.

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

• Kholodenko IV and Konstantin NY. Cellular Mechanisms of liver regeneration and cell-based therapies of liver diseases. BioMed Res Internat 2017, https://doi.org/10.1155/2017/8910821.
• Michalopoulos GK, DeFrances MC: Liver regeneration. Science 276:60, 1997.

Send comments to Richard.Bowen@colostate.edu