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How does the human liver regenerate? The science and latest insights

The liver is a remarkable human organ with a high regenerative capacity and complex functions. The phenomenal capacity of the liver to regenerate has been observed over many centuries in many animals as well.  Even if more than 50% of its overall mass is damaged, it can regenerate itself completely.

Regeneration of the liver was studied when a surgical procedure was performed in rodents (rats and mice) in which 2/3 of the liver mass (66%) was removed, a technique known as 2/3 partial hepatectomy (PHx). Within 7-10 days the liver regained its original size, and functions.

This procedure has been adopted in humans when there is liver damage (cirrhotic liver disease, acute liver failure) liver injury, or tumor/metastasis, or even genetic defects in patients needing large liver resections or transplantation when the liver injury is beyond its ability to regenerate on it’s own.

Three phases have been described in the liver regeneration process, although the underlying mechanisms are still poorly understood. The regenerative response to PHx involves numerous coordinated events occurring at the molecular, cellular, and tissue levels:

Phase One —

The events occurring in the early period of 0–5 h after PHx are referred to the priming phase. In a typical wound healing scenario, tissue injury involves capillary vascular networks resulting in extravasation of blood, accompanied by local release of coagulation factors, platelets, growth factors, etc. However, after PHx, despite there being no extravasation of whole blood, the hemodynamic alterations induce a global spectrum of events across the entire liver that resembles a wound healing response. The liver cells, the hepatocytes are prompted to answer to growth factors. PHx induces rapid induction of more than 100 genes not expressed in normal liver.

Phase Two —

The activation of growth factor receptors, epidermal growth factor receptor (EGFR) and c-Met are both essential for liver regeneration. Many adjustments are made to the hepatocytes, so that they can deliver all essential hepatic functions while going through cell proliferation. This is the cell proliferation phase by more than 95% of hepatocytes during 48 h.

It is truly amazing that the support provided by liver to the whole body is not perceptibly diminished during the regeneration phase.

Biochemical changes include an increase in activity of urokinase plasminogen activator (uPA). Urokinase is known to activate matrix remodeling, seen in most tissues during wound healing and also in liver regeneration. The increase in activity of  uPA throughout the entire liver starting as early as 5 min after PHx. 

Proliferating hepatocytes also are capable of transdifferentiating into other cell types such as those of the biliary system. Thus, hepatocytes may be regarded as committed unipotent cells reproducing themselves.

Regeneration after PHx is also associated with hemodynamic changes. There is approximately a three-fold increase of portal pressure. This induces proliferation of several liver cell types: hepatocytes, stellate cells, bile duct epithelium, hepatic macrophages (Kupffer cells), and fenestrated endothelium of vascular sinusoids to make up the organ. 

Phase Three —

Finally, the last step of the liver regeneration process is cessation of proliferation. Until now, pathways identified as important inhibitors of liver regeneration during the termination phase included transforming growth factor-β and integrin signaling, which mediates communication between the extracellular matrix and epithelial cells.

A key endpoint of liver regeneration is the restoration of the total number and mass of hepatocytes, the main functional cells of the liver responsible for delivering most of the hepatic functions important for body homeostasis.

Full functional restoration should involve restitution of all functions of the normal liver including control of blood sugar levels, production of albumin, blood clotting factors and other vital proteins, bile secretion, and neutralization of poisonous substances.

In humans, among factors affecting restoration time most are the extent of liver damage, diseases of liver parenchyma, age, and portal pressure.