Spatial heterogeneity in the mammalian liver

Hepatocytes operate in highly structured repeating anatomical units termed liver lobules. Blood flow along the lobule radial axis creates gradients of oxygen, nutrients and hormones, which, together with morphogenetic fields, give rise to a highly variable microenvironment. In line with this spatial variability, key liver functions are expressed non-uniformly across the lobules, a phenomenon termed zonation. Technologies based on single-cell transcriptomics have constructed a global spatial map of hepatocyte gene expression in mice revealing that ~50% of hepatocyte genes are expressed in a zonated manner. This broad spatial heterogeneity suggests that hepatocytes in different lobule zones might have not only different gene expression profiles but also distinct epigenetic features, regenerative capacities, susceptibilities to damage and other functional aspects. Here, we present genomic approaches for studying liver zonation, describe the principles of liver zonation and discuss the intrinsic and extrinsic factors that dictate zonation patterns. We also explore the challenges and solutions for obtaining zonation maps of liver non-parenchymal cells. These approaches facilitate global characterization of liver function with high spatial resolution along physiological and pathological timescales. Key hepatic functions are expressed non-uniformly across liver lobules, a phenomenon termed zonation. Here, Ben-Moshe and Itzkovitz discuss the principles of liver zonation, the intrinsic and extrinsic factors that dictate zonation patterns and new genomic approaches for studying zonation of parenchymal and non-parenchymal cells Key points Hepatocytes residing along the lobule porto-central axis are exposed to different microenvironments, resulting in spatial zonation of liver tasks. Single-cell technologies have enabled the reconstruction of zonation patterns for the global hepatocyte transcriptome, revealing principles of liver tissue organization. Examples of optimal features of hepatocyte zonation include the assignment of energetically demanding tasks to highly oxygenated zones, spatial recycling of material and production line patterns. Sequencing pairs of hepatocytes and adjacent non-parenchymal cells enables reconstruction of global zonation patterns of other liver cell types. Liver zonation can give rise to zonated patterns of liver pathologies. Zonation of gene expression is a prominent feature in other metabolic organs such as the intestine and the kidney.