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.

哺乳动物肝脏由称为小叶的重复六边形单元组成。空间分辨的单细胞转录组学研究表明，约有一半的肝细胞基因在小叶上差异表达，但技术局限性阻碍了其他肝细胞特征的相似全球空间图的重建。在这里，我们展示了如何使用分区的表面标记物以高空间分辨率从定义的小叶区域对肝细胞进行分类。我们应用转录组学，microRNA（miRNA）阵列测量和质谱蛋白质组学来重建多个分区特征的空间图集。我们证明，蛋白区带与信使RNA区带在很大程度上重叠，只有门静脉周围的HNF4α例外。我们确定了miRNA的分区，例如miR-122，以及miRNA及其肝细胞靶基因的反向分区，强调了通过分区的mRNA降解对基因表达水平的潜在调控。在靶标中，我们发现了中心周围的Wingless相关整合位点（Wnt）受体Fzd7和Fzd8和门静脉Wnt抑制剂Tcf7l1和Ctnnbip1。我们的方法有助于在肝脏和其他结构化组织中重建具有多个细胞特征的空间地图集。