Project Details
Projekt
The role of liver sinusoidal endothelial cell (LSEC) ultrastructure for cellular Interactions in the scenario of hepatic damage and regeneration visualized by super-resolution optical microscopy
Subject Area
General and Visceral Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 540217954
The human liver is the largest internal organ of the human body and indispensable for the maintenance of physiological homeostasis. Essential functions of the liver include uptake and metabolism of nutrients, synthesis of glycogen, lipids, amino acids and hormones, and the production and secretion of serum proteins including various lipoproteins, albumin, and the constituents of the coagulation system. Within the liver blood is rapidly distributed into smaller caliber vessels that end in hepatic capillaries of 5 to 10 μm diameter, termed sinusoidal vessels. Strands of hepatocytes, termed trabeculae, which at their apical junction form bile canaliculi, embed the sinusoidal vessels and together, hepatocytes and endothelial cells constitute the functional units of the liver. Sinusoidal liver endothelial cells (LSECs) are a highly specialized type of endothelium with unique morphology and functions. LSECs contain many small transmembrane pores, or fenestrations, with average diameters of 100 – 150 nm, within a range of 50 – 300 nm, which provide open channels between the sinusoidal blood and the subendothelial space, the “Space of Disse”, facilitating the transfer of substrate between the blood and the parenchymal hepatocytes. Despite their importance, very little is known about the dynamic structure and function of LSEC fenestrations, because their diameter is well below the optical resolution limit and there are no specific cell surface markers for these structures. Adding to this difficulty is the fact that in tissue these cells line the interior of highly branched blood vessels, the sinusoids, with an inner diameter of less than 10 μm auskleiden, was sie zu m, which makes them an extremely challenging target for invivo imaging. Because of their minute size, in the past, LSEC fenestrations were primarily studied by electron microscopy, which requires substantial sample preparation and can suffer from alterations and artifacts due to the invasive nature of this sample preparation. We hypothesize that hepatic injury specifically results in relevant morphological changes of LSECs. Latter includes capillarization with the loss of fenestrae and appearance of a basement membrane leading to LSEC-dysfunction. Such alterations in LSEC ultrastructure may further influence interactions with platelets, microparticles and homing cells, as previously postulated for hepatically homing tumor cells. In this project, we plan to determine how LSECs are affected in their morphology and subsequently involved in physiological reactions to different forms of liver damage and ensuing hepatic regeneration sequences. We will demonstrate the central role of LSEC to that respect as conductors in various variants of complex orchestrated liver damage and consequent homing and repair mechanisms, respectively. Insights gathered in this proposal will identify novel therapeutic strategies for liver related disease.
DFG Programme
Research Grants
International Connection
Belgium, Norway
Cooperation Partners
Professor Leo van Grunsven; Professor Dr. Peter McCourt
