Signals and cells involved in regulating liver regeneration

Abstract

Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size.

Figure 1

Architecture of the liver. (a) Schematic depicting the architecture and cell type composition of the hepatic sinusoid. Blood enters the lobule from branches of the portal vein (PV) and hepatic artery (HA) and progresses through the sinusoidal capillaries, collecting at the central veins (CV). Bile flows in the opposite direction towards the portal triad and exits through the bile ducts (BD). Hepatocytes are lined up along the sinusoids in “plates” 1-2 hepatocytes thick. Hepatic stellate cells reside in between the sinusoidal endothelial cells and hepatocytes in the “space of Disse”. (b) Diagram illustrating the organization of the hepatic lobule, including vascular structures and relative zonality of the lobule. This unit is repeated throughout the liver. Representative plates of hepatocytes are shown for orientation; these rows of hepatocytes would fill the entire lobule and be lined with sinusoids.

Figure 2

Signals and cells contributing to cell repopulation during liver regeneration. (a) Upon loss of two-thirds of the liver mass after PHx, molecular signals from several cell types contribute to hepatocyte repopulation during regeneration. (b) Both hepatocytes and cholangiocytes undergo self-renewal in normal regeneration; however, transdifferentiation can occur via the relationships indicated. Dotted arrows indicate relationships based on newly emerging literature.