Dual modulation of human hepatic zonation via canonical and non-canonical Wnt pathways

Abstract

The hepatic lobule is divided into three zones along the portal-central vein axis. Hepatocytes within each zone exhibit a distinctive gene expression profile that coordinates their metabolic compartmentalization. The zone-dependent heterogeneity of hepatocytes has been hypothesized to result from the differential degree of exposure to oxygen, nutrition and gut-derived toxins. In addition, the gradient of Wnt signaling that increases towards the central vein seen in rodent models is believed to play a critical role in shaping zonation. Furthermore, hepatic zonation is coupled to the site of the homeostatic renewal of hepatocytes. Despite its critical role, the regulatory mechanisms that determine the distinctive features of zonation and its relevance to humans are not well understood. The present study first conducted a comprehensive zone-dependent transcriptome analysis of normal human liver using laser capture microdissection. Upstream pathway analysis revealed the signatures of host responses to gut-derived toxins in the periportal zone, while both the canonical Wnt pathway and the xenobiotic response pathway govern the perivenular zone. Furthermore, we found that the hypoxic environment of the perivenular zone promotes Wnt11 expression in hepatocytes, which then regulates unique gene expression via activation of the non-canonical Wnt pathway. In summary, our study reports the comprehensive zonation-dependent transcriptome of the normal human liver. Our analysis revealed that the LPS response pathway shapes the characteristics of periportal hepatocytes. By contrast, the perivenular zone is regulated by a combination of three distinct pathways: the xenobiotic response pathway, canonical Wnt signaling, and hypoxia-induced noncanonical Wnt signaling. The distinct gene expression profile of cells at the centre and periphery of liver lobules is maintained by different signaling pathways. Depending on their location, liver cells are exposed to different levels of oxygen, nutrients and toxins, and express particular genes. To understand how these gene signatures are established, Takeshi Saito at the University of Southern California, Los Angeles, and colleagues analysed the gene expression profile of human liver cells from different areas or ‘zones’ obtained from laser captured microdissection apparoach. They found that in cells located next to portal veins, which are exposed to high levels of gut-derived toxins, gene expression is governed by a signaling pathway triggered by microbial compounds. In contrast, the gene expression regulation in peri-central vein zone is far more complex as it is goverend by three distinct mechanisms: 1) canonical Wnt Pathway, an evolutionarily conserved pathway crucial to development, 2) non-canoical Wnt signaling pathway triggered by secreted signaling protein Wnt11 that is induced by the low oxygen, 3) xenobiotics metabolizm pathway.