Liver zonation, revisited

Abstract

The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen and nutrient levels across the hepatic lobule. However, recent advances in single-cell genomics technologies, including single-cell and nuclei RNA sequencing, and the rapidly evolving fields of spatial transcriptomic and proteomic profiling have greatly increased our understanding of liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect liver zonation at unprecedented resolution and how this new information should facilitate the emergence of novel precision medicine-based therapies for patients with liver disease.

FIGURE 1

Technologies driving increased understanding of liver zonation. Transformative experimental strategies are being leveraged to dissect liver zonation at unprecedented resolution, including snRNA‐Seq and scRNA‐Seq,^{[ 52 ]} multiplex smFISH,^{[ 49 ]} spatial transcriptomics, spatial mass spectrometry,^{[ 31 ]} novel lineage tracing mouse models,^{[ 43 ]} and multimodality readouts such as the combination of ATAC‐Seq^{[ 67 ]} with snRNA‐Seq. Created with BioRender.com

FIGURE 2

Hepatocyte zonation during homeostasis and regeneration. Through novel and distinct but complementary lineage tracing models, all hepatocytes have been shown to possess proliferative potential,^{[ 35} , ⁴⁰ , ⁴¹ , ⁴³ , ^{44 ]} with midzonal hepatocytes primarily responsible for proliferation during homeostasis,^{[ 43} , ^{44 ]} compared with regional or diffuse hepatocyte proliferative responses following injury. In homeostasis, hepatocyte gene expression varies across the lobule,^{[ 26} , ²⁷ , ²⁸ , ²⁹ , ^{30 ]} with distinct expression profiles for pericentral, midzonal, and periportal hepatocytes. Created with BioRender.com

FIGURE 3

Hepatic nonparenchymal cell zonation. Immune zonation is driven by gut‐derived microbiota in the portal circulation, activating Myd88 signaling in LSECs and modulating ECM characteristics and therefore chemokine gradients.^{[ 59 ]} Periportal accumulation of Kupffer cells, NK T cells, neutrophils, and CD8+ T cells is observed.^{[ 59 ]} Tolerogenic CD68+ Marco+ macrophages occupy the periportal niche.^{[ 28 ]} Variable gene expression is also observed in endothelial cells and HSCs across the lobule. Periportal HSCs are NGFR+ and pericentral HSCs are Adamstl2+,^{[ 54 ]} whereas endothelial cells exhibit a spectrum of transcriptomic profiles across the hepatic lobule^{[ 49 ]}. Created with BioRender.com