Immunohistochemistry-compatible gel-assisted mass spectrometry imaging

Authors

Hibbard, M. C., Chan, Y. H., Dobbelmann, H. P., Pathmasiri, K. C., Cologna, S. M., Gao, R.

Abstract

While lipids are fundamental to cellular signaling and structure, probing native lipid compositions and distributions across complex tissue architectures at single-cell resolution remains challenging due to inherent trade-offs in spatial resolution, sensitivity, and molecular coverage in current spatial lipidomics methods. Here, we report a multimodal imaging approach that seamlessly integrates gold-standard immunohistochemical labeling with gel-assisted mass spectrometry imaging to enable cell-type-specific, single-cell spatial lipidomics with modern instrumentation. Using intact brain tissue as a testbed, we demonstrate in situ measurement of cerebellar Purkinje cells and spatially mapped lipids across timepoints and cerebellar subregions within the pathological landscape of a neurodegenerative, lysosomal storage disorder. With single-cell lipidomic profiling, we delineated spatiotemporally distinct accumulation of specific glycosphingolipids and phospholipids within Purkinje cells and non-Purkinje cells in the diseased brain. Furthermore, unsupervised single-cell lipidomic clustering elucidated disease-progression- and subregion-dependent molecular divergence between healthy and neurodegenerative states within the cerebellum.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Aug 2026.

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