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Multiscale topology classifies cells in subcellular spatial transcriptomics.

Published version
Peer-reviewed

Repository DOI


Change log

Authors

Benjamin, Katherine  ORCID logo  https://orcid.org/0000-0001-8152-7063
Bhandari, Aneesha 
Kepple, Jessica D 
Qi, Rui 
Shang, Zhouchun 

Abstract

Spatial transcriptomics measures in situ gene expression at millions of locations within a tissue1, hitherto with some trade-off between transcriptome depth, spatial resolution and sample size2. Although integration of image-based segmentation has enabled impactful work in this context, it is limited by imaging quality and tissue heterogeneity. By contrast, recent array-based technologies offer the ability to measure the entire transcriptome at subcellular resolution across large samples3-6. Presently, there exist no approaches for cell type identification that directly leverage this information to annotate individual cells. Here we propose a multiscale approach to automatically classify cell types at this subcellular level, using both transcriptomic information and spatial context. We showcase this on both targeted and whole-transcriptome spatial platforms, improving cell classification and morphology for human kidney tissue and pinpointing individual sparsely distributed renal mouse immune cells without reliance on image data. By integrating these predictions into a topological pipeline based on multiparameter persistent homology7-9, we identify cell spatial relationships characteristic of a mouse model of lupus nephritis, which we validate experimentally by immunofluorescence. The proposed framework readily generalizes to new platforms, providing a comprehensive pipeline bridging different levels of biological organization from genes through to tissues.

Description

Keywords

Animals, Female, Humans, Mice, Cells, Disease Models, Animal, Fluorescent Antibody Technique, Gene Expression Profiling, Kidney, Lupus Nephritis, Reproducibility of Results, Transcriptome, Intracellular Space

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

630

Publisher

Springer Science and Business Media LLC