Spatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury

Peter Androvic, Martina Schifferer, Katrin Perez Anderson, Ludovico Cantuti-Castelvetri, Hanyi Jiang, Hao Ji, Lu Liu, Garyfallia Gouna, Stefan A. Berghoff, Simon Besson-Girard, Johanna Knoferle, Mikael Simons and Ozgun Gokce ()
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Peter Androvic: University Hospital of Munich, LMU Munich
Martina Schifferer: German Center for Neurodegenerative Diseases (DZNE)
Katrin Perez Anderson: University Hospital of Munich, LMU Munich
Ludovico Cantuti-Castelvetri: German Center for Neurodegenerative Diseases (DZNE)
Hanyi Jiang: German Center for Neurodegenerative Diseases (DZNE)
Hao Ji: University Hospital of Munich, LMU Munich
Lu Liu: University Hospital of Munich, LMU Munich
Garyfallia Gouna: German Center for Neurodegenerative Diseases (DZNE)
Stefan A. Berghoff: German Center for Neurodegenerative Diseases (DZNE)
Simon Besson-Girard: University Hospital of Munich, LMU Munich
Johanna Knoferle: German Center for Neurodegenerative Diseases (DZNE)
Mikael Simons: University Hospital of Munich, LMU Munich
Ozgun Gokce: University Hospital of Munich, LMU Munich

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Understanding the complexity of cellular function within a tissue necessitates the combination of multiple phenotypic readouts. Here, we developed a method that links spatially-resolved gene expression of single cells with their ultrastructural morphology by integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) and large area volume electron microscopy (EM) on adjacent tissue sections. Using this method, we characterized in situ ultrastructural and transcriptional responses of glial cells and infiltrating T-cells after demyelinating brain injury in male mice. We identified a population of lipid-loaded “foamy” microglia located in the center of remyelinating lesion, as well as rare interferon-responsive microglia, oligodendrocytes, and astrocytes that co-localized with T-cells. We validated our findings using immunocytochemistry and lipid staining-coupled single-cell RNA sequencing. Finally, by integrating these datasets, we detected correlations between full-transcriptome gene expression and ultrastructural features of microglia. Our results offer an integrative view of the spatial, ultrastructural, and transcriptional reorganization of single cells after demyelinating brain injury.

Date: 2023
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DOI: 10.1038/s41467-023-39447-9

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