Spatially resolved integrative analysis of transcriptomic and metabolomic changes in tissue injury studies

Recent developments in spatially resolved -omics have enabled studies linking gene expression and metabolite levels to tissue morphology, offering new insights into biological pathways. By capturing multiple modalities on matched tissue sections, one can better probe how different biological entities interact in a spatially coordinated manner. However, such cross-modality integration presents experimental and computational challenges. To align multimodal datasets into a shared coordinate system and facilitate enhanced integration and analysis, we propose MAGPIE (Multi-modal Alignment of Genes and Peaks for Integrated Exploration), a framework for co-registering spatially resolved transcriptomics, metabolomics, and tissue morphology from the same or consecutive sections. We illustrate the generalisability and scalability of MAGPIE on spatial multi-omics data from multiple tissues, combining Visium with both MALDI and DESI mass spectrometry imaging. MAGPIE was also applied to newly generated multimodal datasets created using a specialised experimental sampling strategy to characterise the metabolic and transcriptomic landscape in an in vivo model of drug-induced pulmonary fibrosis and to showcase the linking of small-molecule co-detection with endogenous responses in lung tissue. MAGPIE highlights the refined resolution and increased interpretability of spatial multimodal analyses in studying tissue injury, particularly in pharmacological contexts, and offers a modular, accessible computational workflow for data integration. Overall design: A male Wistar Han rat (n=1) was subjected to daily inhalation exposure via snout-only administration for 14 days with 15 mg/kg/day of the AZX test formulation of AZX (10%), MPEG-2000-DSPE (1.25%), trileucine (5%), and trehalose (83.75%), in a flowpast exposure chamber. The rat was purchased from Charles River (Germany) at 7 weeks and were 10 weeks at the start of dosing. Animal handling conformed to standards established by the Council of Europe ETS123 AppA, the Helsinki Convention for the Use and Care of Animals, Swedish legislation, and AstraZeneca global internal standards. All mouse experiments were approved by the Gothenburg Ethics Committee for Experimental Animals in Sweden and conformed to Directive 2010/63/EU. The present study was approved by the local Ethical committee in Gothenburg (EA000680-2017) and the approved site number is 31-5373/11.