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Abstract

The mouse model has been at the forefront of biomedical research and discovery for over a century, significantly advancing our understanding of disease. However, a fundamental gap persists in our comprehension of the complete spatial cellular and transcriptional profile of the mouse body in both health and disease, which hinders a comprehensive understanding of disease mechanisms and molecular dysfunction. Here, we describe Array-seq, a novel method that repurposes classical oligonucleotide microarrays for spatial transcriptomics profiling, achieving an 11.31 cm2 area coverage with 30 µm resolution. We demonstrated that the large surface area of Array-seq slides enables the generation of spatial transcriptomes at high throughput by profiling multi-organ sections, in three dimensions by processing serial sections from one sample, and across whole human organs using spleen sections. Additionally, we developed a novel sectioning method using adhesive film to transfer whole mouse sections to Array-seq slides, preserving the high histological quality of such large and heterogeneous sections. This enables spatial transcriptomics analysis and mapping of organs, tissue subregions, and cell types of the adult mouse model. By applying this technology to an endotoxemia mouse model of sepsis, Array-seq identified spatial patterns of inflammation associated genes and cell type changes across the mouse body. This identified PLA2G5 as a critical mediator in the pathogenesis of the disease, operating as a "self-venom" that disrupts red blood cell integrity and iron metabolism. Our work developing Array-seq demonstrates a versatile tool for spatial transcriptomics, addressing key limitations in the field by offering high-throughput capabilities, large-scale spatial mapping, and integration with histology. This technology presents a new path forward for profiling diseases at scale, providing broader contexts for disease investigation and therapeutic profiling.

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