Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver

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.

SpatialDEG: Identification of differentially expressed genes by leveraging spatial information in spatially resolved transcriptomic studies

“…Among the genes that were spatially differentially expressed, Mup1 , which is a regulator of glucose and lipid metabolism in the mouse [21], was identified in both pairs HFD1 vs WT1 and HFD3 vs WT1. Similarly, CYP2E1 , identified in both HFD1 vs WT1 and HFD3 vs WT1, belongs to the cytochrome P450 family, is involved in xenobiotic metabolism, and plays an important role during catabolic processes [7, 6]. Additionally, the higher expression levels of CYP2A5 in HFD-fed mice are in agreement with the pattern described in a previous report [19].…”

Heterogeneity and Function of Kupffer Cells in Liver Injury

“…Therefore, studies are also trying to unveil KC heterogeneity based on their localization. The existing findings support the view that KCs prefer to locate in the periportal and mid zones (adhere to the portal vein) ( 7 , 39 , 40 ). The portal vein-adhering localization of KCs is maintained by endothelial MYD88-mediated CCL9 gradients ( 40 ) and gut microbiota derived commensal D-lactate ( 42 ).…”

“…Finally, KC heterogeneity might also be determined by localization. In terms to the anatomical structure and transcriptional differences, hepatic lobule is heterogeneity and is separated into periportal, mid and pericentral zones ( 39 ). Based on it, the metabolic and immune zonation of hepatic lobule have been studied ( 40 , 41 ).…”

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

“…Furthermore, preferential effects on the periportal and pericentral regions have been suggested for vitamin E and cysteamine, and PPARγ and FXR agonists, respectively, as per several randomized clinical trials [ 67 , 68 , 69 ]. Therefore, to understand the pathogenesis of NASH and the mechanism of therapeutic efficacy of the Pema and Tofo combination, it will be necessary to explore the spatial gene expression profile of hepatocytes and non-parenchymal cells using scRNA-seq and slide seq technologies [ 70 , 71 , 72 ].…”