Spatial multiomics identifies rheumatoid arthritis synovial niches and de-novo laminar histological patterns of fibroblasts subtypes
- 1Pathology Department, Immunology Discovery Research, AbbVie Bioresearch Center
- 2Immunology Discovery Research, AbbVie, Cambridge Research Center
- 3Immunology Discovery Research, Research & Development, AbbVie Inc.
Abstract
Introduction: Spatial omic technologies provide insight into molecular architecture and spatial cellular organization within tissue. In rheumatoid arthritis (RA), single-cell RNA sequencing and low-resolution spatial transcriptomics have advanced the understanding of synovial biology. However, single-cell spatial resolution using multiple spatial platforms to comprehensively map the immune and stromal cell organization as well as topographical cellular interactions in the RA synovium remain limited.
Methods: We integrated single-cell and bulk spatial transcriptomics (CosMx and Xenium, and Visium, respectively) as well as spatial LC/MS proteomics and a multiplex immunohistochemical protein panel in the histological evaluation of a non-clinical cohort of six RA, three osteoarthritis (OA) and three healthy (NH) arthroscopic synovial biopsies. The histopathological observations were integrated with Xenium-based spatial computational analyses in the RA and NH synovium to define fibroblast organization and spatial relationships in RA compared to the NH synovium.
Results: Cross-platform comparisons demonstrated a strong concordance in cellular composition and microanatomical localization and highlighted the strengths of each technology, with single-cell spatial analysis providing higher cellular resolution, but reduced molecular depth. Comparison of single-cell spatial transcriptomics and LC/MS proteomics also demonstrated concordance, but revealed region-specific expression of fibroblast-associated genes and proteins. Spatial mapping in our large biopsies identified a previously unrecognized laminar organization of up to nine fibroblast subtypes spanning the lining and sublining regions of RA synovium, distinct from NH. Spatial computational pathology analyses showed that specific fibroblast subtypes preferentially localized within lymphoid (CD74+ and CXCL12+), vascular (NOTCH3+ and mural) and stromal (POSTN+, DKK3+ and CD34+) niches. Pathway enrichment analyses further implicated specific biological functions to the fibroblast subtypes that were linked to their microenvironment.
Conclusion: This multimodal spatial molecular pathology study indicates that in RA, fibroblast subtypes expand, spatially reorganize, and establish specialized tissue niches that likely contribute to disease pathogenesis. These findings provide a high-resolution spatial framework and support future spatial multiomics studies aimed at identifying fibroblast ecotypes in the context of treatment naïve, treatment-responsive and treatment-refractory RA patients to identify tissue-level spatial signatures associated with inadequate response to treatments.
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BibTeX
@article{siso2026spatial,
title = {{Spatial multiomics identifies rheumatoid arthritis synovial niches and de-novo laminar histological patterns of fibroblasts subtypes}},
author = {Sílvia Sisó and Archana Iyer and Vineeth Raghuram and Neha Chaudhary and Heather Knight and Fei Wang and Ioan Filip and Lori Duggan and Xue Wang and Katherine Naughton and Terry Melim and Anna Yarilina and Yingli Yang and Jocelyn Rivas and Abby McCarthy and Yu Tian and Dan Chang and Timothy R.D.J. Radstake and Melanie C. Ruzek and Annette Schwartz-Sterman},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1883263},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1883263/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Spatial multiomics identifies rheumatoid arthritis synovial niches and de-novo laminar histological patterns of fibroblasts subtypes
AU - Sílvia Sisó
AU - Archana Iyer
AU - Vineeth Raghuram
AU - Neha Chaudhary
AU - Heather Knight
AU - Fei Wang
AU - Ioan Filip
AU - Lori Duggan
AU - Xue Wang
AU - Katherine Naughton
AU - Terry Melim
AU - Anna Yarilina
AU - Yingli Yang
AU - Jocelyn Rivas
AU - Abby McCarthy
AU - Yu Tian
AU - Dan Chang
AU - Timothy R.D.J. Radstake
AU - Melanie C. Ruzek
AU - Annette Schwartz-Sterman
PY - 2026
DA - 2026/10/16
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1883263
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1883263/full
AB - Introduction: Spatial omic technologies provide insight into molecular architecture and spatial cellular organization within tissue. In rheumatoid arthritis (RA), single-cell RNA sequencing and low-resolution spatial transcriptomics have advanced the understanding of synovial biology. However, single-cell spatial resolution using multiple spatial platforms to comprehensively map the immune and stromal cell organization as well as topographical cellular interactions in the RA synovium remain limited. Methods: We integrated single-cell and bulk spatial transcriptomics (CosMx and Xenium, and Visium, respectively) as well as spatial LC/MS proteomics and a multiplex immunohistochemical protein panel in the histological evaluation of a non-clinical cohort of six RA, three osteoarthritis (OA) and three healthy (NH) arthroscopic synovial biopsies. The histopathological observations were integrated with Xenium-based spatial computational analyses in the RA and NH synovium to define fibroblast organization and spatial relationships in RA compared to the NH synovium. Results: Cross-platform comparisons demonstrated a strong concordance in cellular composition and microanatomical localization and highlighted the strengths of each technology, with single-cell spatial analysis providing higher cellular resolution, but reduced molecular depth. Comparison of single-cell spatial transcriptomics and LC/MS proteomics also demonstrated concordance, but revealed region-specific expression of fibroblast-associated genes and proteins. Spatial mapping in our large biopsies identified a previously unrecognized laminar organization of up to nine fibroblast subtypes spanning the lining and sublining regions of RA synovium, distinct from NH. Spatial computational pathology analyses showed that specific fibroblast subtypes preferentially localized within lymphoid (CD74+ and CXCL12+), vascular (NOTCH3+ and mural) and stromal (POSTN+, DKK3+ and CD34+) niches. Pathway enrichment analyses further implicated specific biological functions to the fibroblast subtypes that were linked to their microenvironment. Conclusion: This multimodal spatial molecular pathology study indicates that in RA, fibroblast subtypes expand, spatially reorganize, and establish specialized tissue niches that likely contribute to disease pathogenesis. These findings provide a high-resolution spatial framework and support future spatial multiomics studies aimed at identifying fibroblast ecotypes in the context of treatment naïve, treatment-responsive and treatment-refractory RA patients to identify tissue-level spatial signatures associated with inadequate response to treatments.
SN - 1664-3224
ER -