ArticlebioRxiv : the preprint server for biology2024
Single-cell spatial transcriptomics of fixed, paraffin-embedded biopsies reveals colitis-associated cell networks.
Elvira Mennillo, Madison L Lotstein, Gyehyun Lee, Vrinda Johri, Christina Ekstrand, Jessica Tsui, Julian Hou, Donna E Leet, Jun Yan He, Uma Mahadevan and 5 more
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In one paragraphArticle in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
15 authors.
Elvira MennilloDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-3210-1004 Madison L LotsteinBiomedical Sciences graduate program, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-9653-4968 Gyehyun LeeDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0003-3789-3319 Vrinda JohriUCSF CoLabs Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0001-7341-4675 Christina EkstrandBiomedical Sciences graduate program, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0009-0004-5182-3573 Jessica TsuiUCSF CoLabs Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-1336-6760 Julian HouDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Donna E LeetDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-4494-1705 Jun Yan HeDivision of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
Uma MahadevanDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-3067-8061 Walter EckalbarUCSF CoLabs Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0003-2520-7852 David Y OhDivision of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-3310-0994 Gabriela K FragiadakisBiomedical Sciences graduate program, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0001-9703-2591 Michael G KattahDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-6067-6585 Alexis J CombesDivision of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.ORCID 0000-0002-9110-6542 Funding
Virology CoreP30AI027763 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Monica Gandhi · 1988 to 2026
$93.6MThe role of γδ T cells in fetal and infant immune defense against malariaR01AI093615 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FEENEY, MARGARET E · 2011 to 2025
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$7.2MTissue mechanics reprograms the tissue to malignancy and metastasisR35CA242447 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI VALERIE MARIE WEAVER · 2020 to 2026
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$3.9MImmune determinants of progression from Oral Epithelial Dysplasia to Oral Squamous Cell Carcinoma by precision multiplexed imagingR01DE032033 · NIDCR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Matthew Spitzer · 2022 to 2026
$3.8MNovel patient biomarkers and mechanisms of TKI associated CardiotoxicityR01HL170038 · NHLBI · UT SOUTHWESTERN MEDICAL CENTER · PI Daniel Addison · 2023 to 2026
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6 · The paper itselfAbstract
Background & Aims: Imaging-based, single-cell spatial transcriptomics (iSCST) using formalin-fixed, paraffin-embedded (FFPE) tissue could transform translational research by retaining all tissue cell subsets and spatial locations while enabling the analysis of archived specimens. We aimed to develop a robust framework for applying iSCST to archived clinical FFPE mucosal biopsies from patients with inflammatory bowel disease (IBD). Methods: We performed a comprehensive benchmarking comparison of three iSCST platforms capable of analyzing FFPE specimens. We analyzed FFPE mucosal biopsies (n=57) up to 5 years old from non-IBD controls (HC; n=9) and patients with ulcerative colitis (UC;n=11). After platform-specific cell segmentation, we applied a uniform data processing pipeline to all datasets, including transcript detection, cell annotation, differential gene expression, and neighborhood enrichment. Transcriptomic signatures identified with iSCST were validated using external, publicly available bulk transcriptomic datasets. Results: A custom 290-plex Xenium gene panel exhibited the highest sensitivity and specificity for transcript detection, enabling precise identification and quantification of diverse cell subsets and differentially expressed genes across cell types and disease states. We mapped transcriptionally distinct fibroblast subsets to discrete spatial locations and identified inflammation-associated fibroblasts (IAFs) and monocytes as a colitis-associated cellular neighborhood. We also identified signatures associated with Vedolizumab (VDZ) responsiveness. VDZ non-responders were characterized by an IAF-monocyte transcriptional signature, while responders exhibited enrichment of epithelial gene sets. Conclusions: Our optimized iSCST framework for archived FFPE biopsies provides unique advantages for assessing the role of colitis-associated cellular networks in routinely collected clinical samples. FFPE-based biomarkers could integrate with existing clinical workflows and potentially aid in risk-stratifying patients.
Indexed as
Spatial transcriptomicsulcerative colitisvedolizumab
Identifiers
PMID39605355
PMCPMC11601222
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