Redefining liver zonation

▸ Bahar Halpern K, Shenhav R, Matcovitch–Natan O, et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver Nature 2017;542:352–6.

Hepatocytes in distinct anatomical locations within the liver lobule are thought to have specialised functions, a paradigm termed liver zonation. In this study, the authors use singlemolecule fluorescence in situ hybridisation and single-cell RNA sequencing (scRNA-seq) to define exhaustively the zonation profiles of all liver genes in mice. Using a panel of six zonally distributed genes (Glul, Cyp2e1, Ass1, Asl, Alb, Cyp2f2), they defined a ‘spatial barcode’, whereby the relative expression of these zonal genes could infer the location of a given cell within one of nine lobule layers between the central vein and portal node. They proceeded to perform scRNA-seq on freshly isolated hepatocytes and used expression levels of the spatial barcode genes to assign each sequenced hepatocyte to one of the nine lobule layers. Using this approach, around 50% of the expressed liver genes are spatially zonated, much higher than previous estimates. They proceeded to study the signals that might influence this zonal gene expression profile. In keeping with previous literature, both Wnt-responsive and hypoxia-responsive genes were enriched in the pericentral hepatocytes, while Ras-responsive genes predominated in the periportal region. Functionally, there was a periportal bias for the expression of liver-secreted proteins such as coagulation factors and complement, while pericentral pathways included detoxification and bile acid biosynthesis. Interestingly, expression of genes that encode hepcidin to regulate iron homeostasis was enriched in the midlobular layers. This study has the potential to redefine the traditional view of liver zonation and highlights a potentially more tightly regulated spatial control of liver biology than previously appreciated. Further work to define how such hepatocyte zonation is perturbed in liver disease might yield novel insights …