Spatial sorting enables comprehensive characterization of liver zonation

• Published in: Nature metabolism Vol. 1; no. 9; pp. 899 - 911
• Main Authors: Ben-Moshe, Shani, Shapira, Yonatan, Moor, Andreas E., Manco, Rita, Veg, Tamar, Bahar Halpern, Keren, Itzkovitz, Shalev
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2019
• Subjects: 631/114; 631/553; 692/4020/4021/288; 82/58; Animals; Biomedical and Life Sciences; Gene Expression Profiling; Hepatocytes - metabolism; Humans; Life Sciences; Liver - metabolism; MicroRNAs - metabolism; Protein Transport; RNA, Messenger - metabolism; Single-Cell Analysis - methods
• ISSN: 2522-5812; 2522-5812
• DOI: 10.1038/s42255-019-0109-9

The mammalian liver is composed of repeating hexagonal units termed lobules. Spatially resolved single-cell transcriptomics has revealed that about half of hepatocyte genes are differentially expressed across the lobule, yet technical limitations have impeded reconstructing similar global spatial maps of other hepatocyte features. Here, we show how zonated surface markers can be used to sort hepatocytes from defined lobule zones with high spatial resolution. We apply transcriptomics, microRNA (miRNA) array measurements and mass spectrometry proteomics to reconstruct spatial atlases of multiple zonated features. We demonstrate that protein zonation largely overlaps with messenger RNA zonation, with the periportal HNF4α as an exception. We identify zonation of miRNAs, such as miR-122, and inverse zonation of miRNAs and their hepatocyte target genes, highlighting potential regulation of gene expression levels through zonated mRNA degradation. Among the targets, we find the pericentral Wingless-related integration site (Wnt) receptors
Fzd7
and
Fzd8
and the periportal Wnt inhibitors
Tcf7l1
and
Ctnnbip1
. Our approach facilitates reconstructing spatial atlases of multiple cellular features in the liver and other structured tissues.
The liver is a heterogeneous organ organized in lobules that are radially polarized. The use of single-cell spatial transcriptomics has revealed that half of hepatic genes are differentially expressed across the lobule. Ben-Moshe et al. show how a multi-omics approach, which consists of transcriptomics, micro RNA profiling and proteomics, allows for characterization of liver heterogeneity with higher resolution.