@article{bf35b1a73c58414eb236cad29136dfba,
title = "Spatial sorting enables comprehensive characterization of liver zonation",
abstract = "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 HNF4a 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.",
author = "Shani Ben-Moshe and Yonatan Shapira and Moor, {Andreas E.} and Rita Manco and Tamar Veg and Halpern, {Keren Bahar} and Shalev Itzkovitz",
note = "We thank E. Hagai and the Flow Cytometry Unit (Weizmann Institute of Science) for FACS technical support; T. Ziv and the Smoler Proteomics Center (Technion) for performing the liquid chromatography–tandem mass spectrometry and analysing the results; and D. Pilzer and the Genomic Technologies Unit (Weizmann Institute of Science) for performing the miRNA microarray measurements. We thank all members of the laboratory for valuable comments. S.I. is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, The Leir Charitable Foundations, the Richard Jakubskind Laboratory of Systems Biology, the Cymerman-Jakubskind Prize, The Lord Sieff of Brimpton Memorial Fund, the I-CORE programme of the Planning and Budgeting Committee (grant no. 1902/12), the Israel Science Foundation (grant no. 1486/16), the Broad Institute-Israel Science Foundation (grant no. 2615/18), the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant no. 768956), the Bert L. and N. Kuggie Vallee Foundation, the Howard Hughes Medical Institute (HHMI) International Research Scholar Award (grant no. 55008734), The Wolfson Family Charitable Trust (grant no. 21376) and the Edmond de Rothschild Foundations. Contributions - K.B.H. and S.I. conceived the study. S.B.M. and S.I. designed the experiments. S.B.M. prepared all the samples. S.B.M. and Y.S. analysed the data. A.E.M. contributed to the data analysis. R.M. and T.V. assisted with the immunofluorescence experiments. K.B.H. contributed to establishing the methodology. S.I. supervised the study. S.B.M., Y.S. and S.I. wrote the manuscript. All authors reviewed the manuscript and provided input.",
year = "2019",
month = sep,
day = "16",
doi = "https://doi.org/10.1038/s42255-019-0109-9",
language = "الإنجليزيّة",
volume = "1",
pages = "899--911",
journal = "Nature metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "9",
}