[PDF][PDF] Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases
Med, 2022•cell.com
Background Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis,
inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent
a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of
fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has
limited our understanding of which pathways are shared by multiple diseases. Methods We
profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and …
inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent
a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of
fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has
limited our understanding of which pathways are shared by multiple diseases. Methods We
profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and …
Background
Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.
Methods
We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.
Findings
Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.
Conclusions
This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.
Funding
Grant from F. Hoffmann-La Roche (Roche) AG.
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