Abstract
Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. However, global transcriptional differences across lobular units remain elusive in physical space. Here, we apply Spatial Transcriptomics to perform transcriptomic analysis across sectioned liver tissue. We confirm that the heterogeneity in this complex tissue is predominantly determined by lobular zonation. By introducing novel computational approaches, we enable transcriptional gradient measurements between tissue structures, including several lobules in a variety of orientations. Further, our data suggests the presence of previously transcriptionally uncharacterized structures within liver tissue, contributing to the overall spatial heterogeneity of the organ. This study demonstrates how comprehensive spatial transcriptomic technologies can be used to delineate extensive spatial gene expression patterns in the liver, indicating its future impact for studies of liver function, development and regeneration as well as its potential in pre-clinical and clinical pathology.
Highlights
Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years
The remaining tissue consists of liver non-parenchymal cells (NPCs), including liver endothelial cells (LECs), liver resident macrophages (Kupffer cells) and other immune cells, hepatic stellate cells (HSCs) and other stromal cells, biliary epithelial cells and cell types of the vasculature, which together make up the heterogeneous functional lobular liver environment[7]
Given the strong association between the differentially expressed genes (DEG) in the periportal cluster (PPC) and pericentral cluster (PCC), as well as the convincing demonstration of co-localization with histologically annotated central and portal veins, we aimed to explore whether veins could be computationally annotated solely based on gene expression (Fig. 3d)
Summary
Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. Liver resident cells execute distinct functions along the lobular axis based on their proximity to the CV or the PV8–11 In mice, this spatial division in metabolic functions, known as zonation, is primarily based on the differential expression profiles along the lobular axis and is classically divided into three zones (zone 1–3). Recent findings from single-cell spatial reconstruction approaches suggest that smaller and less abundant NPCs follow distinct spatial expression profiles based on their position along the lobular axis[13,14] These reconstruction approaches: (I) provide an intricate image of the metabolic division of labor within the microenvironment of the liver lobule, (II) identify defining factors of zonation based on differentially expressed genes (DEG) along the lobular axis[12,14,15,16] and (III) represent a fundamental resource for the extensively studied concept of liver zonation[7]. Lobules are situated in varying proximities to the main sources of blood supply, namely the hepatic artery and the portal vein
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