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

Abstract

The hepatic central vein, the initial branch of the hepatic vein, occupies the central position of the classic liver lobule. Endothelial cells of the central vein contain organelles showing activities for protein production and secretion. The endothelium is supported by a thin wall, which contains a collagenous matrix and few myofibroblasts. The ultrastructure of perivenous hepatocytes differs from that of periportal hepatocytes. Perivenous hepatocytes stably express glutamine synthetase serving as a reliable immunohistochemical cell marker. 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 signaling pathways regulate hepatic metabolic zonation and perivenous gene expression. The structures of the molecules of these pathways have been elucidated. Expression levels of glutamine synthetase and cytochrome P4502E1 are indicators 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 towards responder cells have been described. The modes of Wnts and R-spondin3 release from cental vein endothelial cells and their transit in the venular wall towards perivenous hepatocytes are unknown. GS + , Axin2 + , Tbx3 + , HNF4α + and CPS − perivenous hepatocytes were shown to exhibit stem cell properties, subserving homeostatic liver renewal. However, the existence of perivenous stem cells in the liver needs further investigations for validation. The hepatic central vein constitutes an anatomical niche of perivenous hepatocytes and provides a molecular link to perivenous hepatic biology.

A review of hepatic fibrosis‐associated histopathology in aged cadavers

“…The ultrastructure of the central vein endothelial cells was recently described (Mak & Shin, 2021). Moreover, the endothelium secretes Wnts and R‐spondin3, which are involved in regulating perivenous gene expression and maintaining centrilobular metabolic zonation (Mak, 2019a; Mak & Png, 2020). The wall or rim of the normal central vein in humans does not exceed 4 μm in thickness and contains sparse matrix fibrous proteins and cells.…”

“…Zonation reflects the heterogeneity of gene expression and functions of hepatocytes along the centro‐portal axis of the liver lobule. The Wnt/β‐catenin signaling pathway is the master regulator of hepatic zonation (Mak, 2019a). The pathway maintains the metabolic zonation of glutamine synthetase (GS) and cytochrome P4502E1 (CYP2E1), among others, in the centrilobular parenchyma.…”