Spatiotemporal multi-omics atlas of liver homeostasis and regeneration

The mammalian liver is composed of repetitive microstructures termed lobules that are polarized by blood and signaling factors to diversify functions. Single-cell omics and lineage tracing studies are beginning to unravel liver molecular heterogeneity, but the lack of bona fide genome-wide topographic information complicates meaningful interpretations. Here, we have used Stereo-seq (Spatio-Temporal Enhanced REsolution Omics-sequencing) (1,003,867 bins covering an added area of 12.83 square centimeters), combined with single-cell RNA-sequencing (61,618cells), to profile mouse liver homeostasis and a time course of regeneration after partial hepatectomy. Our integrative spatiotemporal analysis accurately resolves the transcriptomic and epigenetic gradients controlling the identity of all liver cell types and their molecular crosstalk in both homeostasis and regeneration. Furthermore, by studying the gene regulatory networks we identify the transcriptional cofactor TBL1XR1 as an inflammation-induced regulator of hepatocyte proliferation that derepresses beta-catenin bound WNT responsive genes. Our comprehensive high-resolution atlas provides the foundation for future spatiotemporal studies of liver malfunction in aging and disease.