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Principles of Liver Regeneration and Growth Homeostasis

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Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ. Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis. They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines. Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function). When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment. In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment. Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly). The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types. © 2013 American Physiological Society. Compr Physiol 3:485‐513, 2013.

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Figure 1. Figure 1.

Schematic diagram of the different growth responses of the liver. In liver regeneration after 2/3 partial hepatectomy (PHx) in rodents, removal of the two major lobes of the liver triggers growth to the two residual lobes, which expand in size to reach in aggregate the total size of the original liver prior to hepatectomy. When PHx is performed and hepatocyte proliferation is suppressed, biliary cells become transformed into “oval” cells (small red oval shapes) that become hepatocytes and restore the liver mass. In augmentative hepatomegaly, increase in liver size beyond the original is induced by a xenobiotic chemical or a native signaling molecule, causing expansion of all liver lobes.

Figure 2. Figure 2.

Schematic diagram of external signaling molecules involved in liver regeneration after 2/3 partial hepatectomy (PHx). A combination of mitogenic growth factors and auxiliary mitogens converge upon hepatocytes to induce entry into the cell cycle. That triggers production of growth signals by hepatocytes, which are directed toward other hepatic cell types, inducing their entry into proliferation and triggering production of growth signals that are directed back to hepatocytes.

Figure 3. Figure 3.

Necrosis of centrilobular areas of the liver lobule following administration of carbon tetrachloride. This is a very common form of liver injury, induced by chemicals that are activated to reactive electrophiles by the CYP family of enzymes (typically localized in the centrilobular hepatocytes). (A) Low power magnification showing the extent of the damage (40×). (B) High power magnification showing details of the necrotic centrilobular areas surrounded by damaged hepatocytes with hydropic degeneration of their cytoplasm.

Figure 4. Figure 4.

Hepatocytes and biliary epithelial cells can function as facultative stem cells for each other. This occurs when either cell compartment is required to proliferate in response to injury or tissue loss, but is unable to do so. Oval cells arise from portal biliary ductules and/or from canals of Hering (ductules lined by biliary epithelial cells and directing flow of bile from hepatocyte canaliculi to portal biliary ductules). Immediate periportal hepatocytes can also transform into biliary epithelial cells.

Figure 1.

Schematic diagram of the different growth responses of the liver. In liver regeneration after 2/3 partial hepatectomy (PHx) in rodents, removal of the two major lobes of the liver triggers growth to the two residual lobes, which expand in size to reach in aggregate the total size of the original liver prior to hepatectomy. When PHx is performed and hepatocyte proliferation is suppressed, biliary cells become transformed into “oval” cells (small red oval shapes) that become hepatocytes and restore the liver mass. In augmentative hepatomegaly, increase in liver size beyond the original is induced by a xenobiotic chemical or a native signaling molecule, causing expansion of all liver lobes.

Figure 2.

Schematic diagram of external signaling molecules involved in liver regeneration after 2/3 partial hepatectomy (PHx). A combination of mitogenic growth factors and auxiliary mitogens converge upon hepatocytes to induce entry into the cell cycle. That triggers production of growth signals by hepatocytes, which are directed toward other hepatic cell types, inducing their entry into proliferation and triggering production of growth signals that are directed back to hepatocytes.

Figure 3.

Necrosis of centrilobular areas of the liver lobule following administration of carbon tetrachloride. This is a very common form of liver injury, induced by chemicals that are activated to reactive electrophiles by the CYP family of enzymes (typically localized in the centrilobular hepatocytes). (A) Low power magnification showing the extent of the damage (40×). (B) High power magnification showing details of the necrotic centrilobular areas surrounded by damaged hepatocytes with hydropic degeneration of their cytoplasm.

Figure 4.

Hepatocytes and biliary epithelial cells can function as facultative stem cells for each other. This occurs when either cell compartment is required to proliferate in response to injury or tissue loss, but is unable to do so. Oval cells arise from portal biliary ductules and/or from canals of Hering (ductules lined by biliary epithelial cells and directing flow of bile from hepatocyte canaliculi to portal biliary ductules). Immediate periportal hepatocytes can also transform into biliary epithelial cells.

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George K. Michalopoulos. Principles of Liver Regeneration and Growth Homeostasis. Compr Physiol 2013, 3: 485-513. doi: 10.1002/cphy.c120014