Frei, A. P. | bioRxiv Science

bioRxiv2023

Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA)

Spatial transcriptomics techniques are able to chart the distribution and localization of cell types and RNA molecules across a tissue. Here, we generated matched sequencing-based (Visium) and hybridization-based (Molecular Cartography) spatial transcriptomics data of human IBD samples. We then developed ISCHIA (Identifying Spatial Co-occurrence in Healthy and InflAmed tissues), a computational framework to analyze the spatial co-occurrence of cell types and transcript species in the tissue environment. ISCHIA revealed tightly associated cellular networks, ligand-receptor interactions enriched in the inflamed human colon, and their associated gene signatures, highlighting the hypothesis-generating power of co-occurrence analysis on spatial transcriptomics data.

systems biology↗

bioRxiv2021

Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Pro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjogrens 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 the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases.

genomics↗