The Hepatic Central Vein: Structure, Fibrosis, and Role in Liver Biology.

The hepatic central vein is a primary source of Wnt2, Wnt9b, and R-spondin3. These angiocrines activate ß-catenin signaling to regulate hepatic metabolic zonation and perivenous gene expression in mice. Little is known about the central vein ultrastructure. Here, we describe the morphological-functional correlates of the central vein and its draining and branching patterns. Central vein fibrosis occurs in liver disease and is often accompanied by perivenous perisinusoidal fibrosis, which may affect perivenous gene expression. We review the biological properties of perivenous hepatocytes and glutamine synthetase that serve as a biomarker of perivenous hepatocytes. Glutamine synthetase and P4502E1 are indicators of ß-catenin activity in centrilobular liver injury and regeneration. The Wnt/ß-catenin pathway is the master regulator of hepatic metabolic zonation and perivenous gene expression and is modulated by the R-spondin-LGR4/5-ZNRF3/RNF43 module. We examined the structures of the molecules of these pathways and their involvements in liver biology. Central vein-derived Wnts and R-spondin3 participate in the cellular-molecular circuitry of the Wnt/ß-catenin and R-spondin-LGR4/5-ZNRF3/RNF43 module. The transport and secretion of lipidated Wnts in Wnt-producing cells require Wntless protein. Secreted Wnts are carried on exosomes in the extracellular matrix to responder cells. The modes of release of Wnts and R-spondin3 from central veins and their transit in the venular wall toward perivenous hepatocytes are unknown. We hypothesize that central vein fibrosis may impact perivenous gene expression. The proposal that the central vein constitutes an anatomical niche of perivenous stem cells that subserve homeostatic hepatic renewal still needs studies using additional mouse models for validation. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1747-1767, 2020. © 2019 American Association for Anatomy.