Liver regeneration is the process by which the liver is able to replace lost liver tissue from growth from the remaining tissue. The liver is the only visceral organ that possesses the capacity to regenerate. The liver can regenerate after either surgical removal or after chemical injury. It is known that as little as 25% of the original liver mass can regenerate back to its full size. The process of regeneration in mammals is mainly compensatory growth because only the mass of the liver is replaced, not the shape. However, in lower species such as fish, both liver size and shape can be replaced.
There are two events in which the liver has the capability to regenerate, one being a partial hepatectomy and the other being damage to the liver by toxins or infection (1). The processes described below deal with the pathways triggered after a partial hepatectomy.
Following the event of partial hepatectomy, there are three phases for the process of regeneration. The first phase is the priming phase and during this portion, hundreds of genes are activated and prepare the liver for regeneration. This priming phase occurs within 0-5 hours after the hepatectomy and deals mainly with events prior to entering the cell cycle and ensuring that hepatocytes can maintain their homeostatic functions. The second phase deals with the activation of various growth factors such as EGFR (epidermal growth factor receptor) and c-Met. These two factors are major components of liver regeneration. The final phase deals with termination of proliferation by TGF-β (transforming growth factor-beta).
Immediately after a hepatectomy, there is an activation of numerous signaling pathways that start the process of regeneration. The first being an increase in urokinase activity. Urokinase is known to activate matrix remodeling. This remodeling causes the release of HGF (hepatic growth factor) and from this release now c-Met can also be activated. EGFR is also activated in the same way as c-Met, and these two growth factors play a major role in the regeneration process. These processes occur outside of the hepatocyte and prime the liver for regeneration. Once these processes are complete, hepatocytes are able to enter the liver to start the process of proliferation. This is because there is a communication between β-catenin (inside the hepatocyte) and the growth factors of EGFR and c-Met (outside the hepatocyte). This communication can occur because of β-catenin and Notch-1 move to the nucleus of the hepatocyte approximately 15-30 minutes after the hepatectomy. The presence of these two proteins increases the regenerative response and the HGF and EGFR act as direct mitogens and can produce a strong mitogenic response for the hepatocytes to proliferate.
After the regeneration process has completed, TGF-β puts an end to the proliferation by inducing apoptosis. TGFβ1 inhibits the proliferation of hepatocytes by repressing HGF. As mentioned above, urokinase activated the release of HGF; therefore, TGFβ1 also represses the urokinase activity. This process is able to bring the hepatocytes back into their quiescent state.
Sometimes, hepatocytes do not have the ability to proliferate and an alternative form of regeneration is able to take place to rebuild the liver. This can happen with the help of biliary epithelial cells having the capability of turning into hepatocytes when the original hepatocytes have problems proliferating. This is due to the fact that biliary cells have two functions, one being the normal transport of bile and the other becoming stem cells for hepatocytes. The same also occurs vice versa, with hepatocytes being able to turn into biliary cells when they cannot proliferate. Both of these kinds of cells are facultative stem cells for each other. Facultative stem cells originally have one fate but upon injury of another type of cell, can function as a stem cell. These two types of cells can repair liver tissue even when the normal mechanism of liver regeneration fails.
The ability for the liver to regenerate is central to liver homeostasis. Because the liver is the main site of drug detoxification, it is exposed to many chemicals in the body which may potentially induce cell death and injury. The liver can regenerate damaged tissue rapidly thereby preventing its own failure. However, a predictor of the true speed of liver regeneration depends on whether Interleukin 6 has overexpression. Liver regeneration is also critical for patients of liver diseases where the partial removal of the liver due to fibrosis or tumor is a common therapy that utilizes the ability of the remaining liver to generate back.
Two main types of models are used to study liver regeneration, including surgical removal, also referred to as partial hepatectomy (PHX), and chemical-induced liver damage. Whereas the mechanisms and kinetics of liver regeneration in these two models are different, many of the same signaling pathways stimulate liver regeneration in both pathways.
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