The polarized architecture of hepatocytes: Regulation by intrinsic and extrinsic factors

Hepatocytes are liver epithelial cells that produce bile. To drain bile, hepatocytes develop a network of small canals that ultimately drain into larger bile ducts, gall bladder, and intestine. The micro-anatomy of this bile canalicular network is unique for hepatocytes and enabled by the unique polarized architecture of individual hepatocytes. The polarized architecture of hepatocytes (i.e., hepatocyte polarity) and the bile canalicular network are crucial for a healthy liver. It is therefore important to know what cellular principles and molecular mechanisms underlie the formation and maintenance of hepatocyte polarity. In larger tube-forming epithelia (such as the intestine and kidney, but also the larger bile ducts in the liver), the (symmetric) orientation of cell division, the cellular micro-environment, and intracellular transport to a single lumen-facing cell surface are crucial for tube formation. How hepatocytes use these design mechanisms to form the bile canalicular network is unknown. This thesis shows that hepatocytes utilize a hepatocyte-specific mode of cell division that is unlike other tube-forming epithelia. This is largely due to the specific activity and expression of molecular switches in hepatocytes, and the specific micro-environment of hepatocytes in the liver. Interestingly, and in contrast to other tube-forming epithelia, hepatocytes are not limited to the formation of a single lumen-facing cell surface during bile canaliculi formation. Thus, hepatocytes use tube-forming design principles in a distinct manner that, we speculate, enables them to form and maintain a functional bile canalicular network. These revelations are important for the (patho)biology of liver diseases such as polycystic liver disease, liver fibrosis, and hepatocellular carcinoma.