Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease

Garrido-Trigo, Alba; Corraliza, A M; Veny, Marisol; Dotti, Isabella; Melón-Ardanaz, Elisa; Rill, Aina; Crowell, Helena L.; Corbí, Ángel L.; Gudiño, Victòria; Esteller, Miriam; Álvarez-Teubel, Iris; Aguilar, Daniel; Masamunt, Maria Carme; Killingbeck, Emily; Kim, Youngmi; Leon, Michael; Visvanathan, Sudha; Marchese, Domenica; Caratù, Ginevra; Martín‐Cardona, Albert; Esteve, María; Panés, Julián; Ricart, E; Mereu, Elisabetta; Heyn, Holger; Salas, Azucena

doi:10.1038/s41467-023-40156-6

Cited by 58 publications

(31 citation statements)

References 61 publications

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“…We chose a permissive threshold of removing cells with fewer than 10 transcripts for Xenium and MERSCOPE, and 20 transcripts for CosMx from downstream analysis. [11, 24, 25] . The tumor TMA consistently had a greater fraction of cells passing filtration, with Xenium retaining the most cells (97.43% breast, 97.10% multi-tissue, 95.08% lung) followed by CosMx (83.41%) and MERSCOPE (68.46% breast (10 µm), 25.77% lung (5 µm) ( Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues

Wang,

Huang,

Nelson

et al. 2023

Preprint

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Emerging imaging spatial transcriptomics (iST) platforms and coupled analytical methods can recover cell-to-cell interactions, groups of spatially covarying genes, and gene signatures associated with pathological features, and are thus particularly well-suited for applications in formalin fixed paraffin embedded (FFPE) tissues. Here, we benchmarked the performance of three commercial iST platforms on serial sections from tissue microarrays (TMAs) containing 23 tumor and normal tissue types for both relative technical and biological performance. On matched genes, we found that 10x Xenium shows higher transcript counts per gene without sacrificing specificity, but that all three platforms concord to orthogonal RNA-seq datasets and can perform spatially resolved cell typing, albeit with different false discovery rates, cell segmentation error frequencies, and with varying degrees of sub-clustering for downstream biological analyses. Taken together, our analyses provide a comprehensive benchmark to guide the choice of iST method as researchers design studies with precious samples in this rapidly evolving field.

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Section: Resultsmentioning

confidence: 99%

Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues

Wang,

Huang,

Nelson

et al. 2023

Preprint

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“… A. Tissue structure of colon (top; Xenium: public data from 10x Genomics, CosMx: Garrido-Trigo et al 23 ), lung cancer (middle, Xenium: public data from 10x Genomics, CosMx: public data from NanoString Technologies), and breast cancer (bottom; Xenium and CosMx provided the Suzuki lab, University of Tokyo). Cell annotations are based on automated annotation from scRNA-seq reference datasets.…”

Section: Resultsmentioning

confidence: 99%

A Comparative Analysis of Imaging-Based Spatial Transcriptomics Platforms

Cook,

Jensen,

Wise

et al. 2023

Preprint

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Spatial transcriptomics is a rapidly evolving field, overwhelmed by a multitude of technologies. This study aims to offer a comparative analysis of datasets generated from leadingin situimaging platforms. We have generated spatial transcriptomics data from serial sections of prostate adenocarcinoma using the 10x Genomics Xenium and NanoString CosMx SMI platforms. Additionally, orthogonal single-nucleus RNA sequencing (snRNA-seq) was performed on the same FFPE tissue to establish a reference for the tumor’s transcriptional profiles. We assessed various technical aspects, such as reproducibility, sensitivity, dynamic range, cell segmentation, cell type annotation, and congruence with single-cell profiling. The practicality of assessing cellular organization and biomarker localization was evaluated. Although fewer genes are measured (CosMx: 960, Xenium: 377, with an overlap of 125), Xenium consistently demonstrates higher sensitivity, a broader dynamic range, and better alignment with single-cell reference profiles. Conversely, CosMx’s out-of-the-box segmentation outperformed Xenium’s, resulting in noticeable transcript misassignment in Xenium within certain tissue areas. However, the impact of this on the cells’ transcriptional profile was minimal. Together, this comprehensive comparison of two leading commercial platforms for spatial transcriptomics provides essential metrics for assessing their performance, offering invaluable insights for future research and technological advancements in this dynamic field.

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“…At the time of this writing, emerging single-cell transcriptome data in mucosal samples reveal the heterogeneity of tissue neutrophils in IBD patients. Noteworthy, A. Garrido-Trigo et al report that, in contrast to UC, the majority of intestinal neutrophils in CD display a marked IFN-response signature ( 26 ). This is in agreement with, and further supports, our transcriptome findings in peripheral neutrophils of CD.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn’s disease through IFNα pathway

Gavriilidis,

Divolis,

Natsi

et al. 2023

Preprint

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Crohn’s disease (CD) is characterized by chronic inflammation and intestinal fibrosis leading to lifelong complications. However, disease pathogenesis is elusive and the therapeutic options are limited. We investigated the interaction between neutrophils and intestinal fibroblasts in the development of CD immunofibrosis. Peripheral neutrophils, enriched neutrophil extracellular traps (eNETs), serum, primary intestinal fibroblasts (PIFs) and intestinal biopsies from CD and ulcerative colitis (UC) patients, and healthy individuals (HI), were studied. Neutrophil-targeted transcriptomics, multi-cytokine profiling and cell-based functional assays at mRNA/protein level were performed. Compared to UC, PIFs from CD patients displayed a distinct fibrotic phenotype characterized by negative Krüppel-like Factor-2 (KLF2) and increased cellular communication network factor-2 (CCN2) expression leading to collagen production. In UC and CD, PIFs-derived IL-8 appears as a culprit chemoattractant of neutrophils in the intestine, where CD neutrophils were accumulated close to fibrotic lesions. Functionally, only CD neutrophilsviaeNETs can induce a CD-like phenotype in HI PIFs, suggesting their fibrotic plasticity. High IFNα in serum and IFΝ-responsive signature in peripheral neutrophils were observed in CD, distinguishing it from UC. Moreover, CD serum can stimulate the release of fibrogenic eNETs from neutrophils in an IFNα-dependent manner, suggesting the priming role of IFNα in circulating neutrophils. Inhibition of eNETs or JAK signaling in neutrophils or PIFs prevented the neutrophil-mediated fibrotic effect on PIFs. Furthermore, serum IFNα and transcripts of key IFN-signaling components in neutrophils were well-correlated with CD severity. This study reveals the important role of IFNα/neutrophil/fibroblast axis in CD immunofibrosis, suggesting candidate biomarkers and putative therapeutic targets.

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Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease

Cited by 58 publications

References 61 publications

Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues

Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues

A Comparative Analysis of Imaging-Based Spatial Transcriptomics Platforms

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn’s disease through IFNα pathway

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