Single-cell spatial reconstruction reveals global division of labour in the mammalian liver

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The mammalian liver consists of hexagon-shaped lobules that are radially polarized by blood flow and morphogens1,2,3,4. Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation5,6, but a detailed genome-wide reconstruction of this spatial division of labour has not been achieved. Here we measure the entire transcriptome of thousands of mouse liver cells and infer their lobule coordinates on the basis of a panel of zonated landmark genes, characterized with single-molecule fluorescencein situhybridization7. Using this approach, we obtain the zonation profiles of all liver genes with high spatial resolution. We find that around 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. These include a spatial order of bile acid biosynthesis enzymes that matches their position in the enzymatic cascade. Our approach can facilitate the reconstruction of similar spatial genomic blueprints for other mammalian organs.

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