Multimodal mass spectrometry imaging identifies cell-type-specific metabolic and lipidomic variation in the mammalian liver

Spatial single-cell omics provides a readout of biochemical processes. It is challenging to capture the transient lipidome/metabolome from cells in a native tissue environment. We employed water gas cluster ion beam secondary ion mass spectrometry imaging ([H2O]n>28K-GCIB-SIMS) at ≤3 μm resolution using a cryogenic imaging workflow. This allowed multiple biomolecular imaging modes on the near-native-state liver at single-cell resolution. Our workflow utilizes desorption electrospray ionization (DESI) to build a reference map of metabolic heterogeneity and zonation across liver functional units at tissue level. Cryogenic dual-SIMS integrated metabolomics, lipidomics, and proteomics in the same liver lobules at single-cell level, characterizing the cellular landscape and metabolic states in different cell types. Lipids and metabolites classified liver metabolic zones, cell types and subtypes, highlighting the power of spatial multi-omics at high spatial resolution for understanding celluar and biomolecular organizations in the mammalian liver. [Display omitted] •Multimodal MSI integrates the spatial multi-omics at tissue and single-cell levels•Dual-SIMS images metabolic states of different cell types in the frozen liver•DESI reveals zonation across liver tissue functional units Tian and Rajbhandari et al. integrated metabolites, lipids, and proteins profiling, using a multimodal MSI workflow, and identified the lipidomic/metabolic signatures in liver functional units and different cell types.