The Hepatic Central Vein: Anatomical and Molecular Links to Perivenous Liver Biology

Abstract

The hepatic central vein, the initial branch of the hepatic veins, occupies the central position in the classic liver lobule.  The endothelial cells of the vein contain organelles showing secretory modality and are supported by a thin wall containing collagenous matrix and a layer of myofibroblasts.  Perivenous hepatocytes differ in ultrastructure from periportal heatocytes and stably express glutamine synthetase serving as a reliable biomarker. Central veins are a primary source of Wnt2, Wnt9b and R-spondin3. These angiocrines participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 signaling modules associated with perivenous hepatocytes. These modules regulate hepatic metabolic zonation and perivenous gene expression. The structures of the molecules of these signaling pathways have been elucidated.  Expression of glutamine synthetase and cytochrome P4502E1 is indicator of   ß-catenin activity in liver injury and regeneration. The production, transport and secretion of lipidated Wnts in Wnt-producing cells and their passage in the extracellular matrix to contact responder cells have been described.  The modes of Wnts and R-spondin3 release from cental vein endothelial cells and passage in the wall matrix to reach perivenous hepatocytes are unknown. GS⁺, Axin2⁺, Tbx3⁺, HNF4a⁺ and CPS^- perivenous hepatocytes exhibit stem cell properties, subserving homeostatic hepatocyte renewal.  The hepatic central vein constitutes an anatomical niche of perivenous hepatocyte stem cells and provides a molecular link to perivenous hepatic biology.