This group has a long-standing interest in the mechanisms of endocytosis. In 2012, we observed that loss of the small GTPase Rab5 in adult mouse liver caused a dramatic reduction in the number of early endosomes, late endosomes, and lysosomes in murine cells. Additionally, these mice exhibited various metabolic phenotypes (Zeigerer et al., 2012). Our research interest has since broadened from molecular mechanisms of endocytosis to the role of the endocytic machinery in cell and tissue function.
The liver as a model organ for cell polarization
The liver is crucial for many physiological processes such as macronutrient metabolism, blood volume regulation, and the breakdown of toxic compounds. It is the only organ that regrows upon dissection and has outstanding regeneration capacities. The liver comprises several cell types, each with its specific function. Almost 80% of the liver consists of parenchymal cells called hepatocytes that are honeycombed by two 3D microcirculatory systems: the sinusoids that transport blood and the bile canaliculi network that drains bile into bile ducts.
How is endocytosis connected to cell polarity?
Hepatocytes are polarized cells, meaning there are functional and spatial differences within the cell. Cellular trafficking and endocytosis are directly responsible for the proper localization of polarity regulators. In contrast to simple polarized cells such as epithelia, hepatocytes possess a belt-like apical membrane that wraps around the entire cell. The apical surfaces of several hepatocytes pair with the neighboring ones to form a small lumen in between. In its entirety, these connected lumina form the bile canalicular network.
This video shows a single hepatocyte (grey) with the apical surface that form the bile canaliculi in green and basal surface that faces towards the sinusoids in magenta. This data is reconstructed from high-resolution 3D microscopy images (Morales-Navarrete et al., 2019). Copyright: MPI-CBG.
Apical bulkheads – a novel player in bile canaliculi formation and maintenance
More recently we found that bile canaliculi formation requires specific extensions of the apical membrane traversing the lumen to ensure their growth as a tubule. We termed these mechanical structures apical bulkheads and found that their assembly requires the endosomal protein Rab35 (Belicova et al., 2021). In a collaboration with the Haas Group at the CSBD, we developed a mechanical model of apical bulkheads and saw that they contribute to withstanding bile pressure in the bile canaliculi (Bebelman, Bovyn et al., 2022).
Rosette structures identified as dilated canaliculi
Also in patients with primary sclerosing cholangitis (PSC), a type of liver disease where bile flow in the liver is impaired, we see apical bulkheads form in the bile canaliculi. Additionally, we found another structure in tissue of PSC patients, called rosettes. These are abnormal liver cells arranged like rose petals around a small opening, a lumen. For a long time, physicians have used liver rosettes as a marker in the diagnosis of cholestatic liver disease, but they did not know what exactly these structures were. We now understand that rosettes form when the pressure in the canaliculi is too high and thus the canaliculus dilates and forms a round lumen (Mayer et al., 2023).
We are currently aiming to understand the molecular components and mechanisms underlying apical bulkhead formation in the healthy and diseased liver.
