TCF21 loss identifies a conserved inflammation-associated fibroblast state across Crohn's disease and ulcerative colitis

Background and Aims: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are associated with stromal remodeling; however, the fibroblast states that contribute to chronic inflammation remain incompletely defined. We aimed to identify conserved pathogenic fibroblast programs across CD and UC and determine whether these states are linked to loss of homeostatic stromal regulators. Methods: We integrated publicly available single-cell RNA sequencing datasets from healthy and inflamed intestinal tissues to define stromal populations across CD, UC, and control samples. Fibroblast subsets were annotated using cluster-specific markers and patient-level abundance analyses. Multiplex immunofluorescence of human gastrointestinal tissue microarrays assessed protein expression. Human colonic fibroblasts were stimulated with IL1B and TNF to model inflammation-associated fibroblast polarization, and restoration of homeostatic factors was evaluated using mRNA-loaded lipid nanoparticles (LNPs). Results: A conserved inflammation-associated fibroblast (IAF) population was expanded in both CD and UC and expressed inflammatory chemokines, matrix-remodeling genes, and activation markers including CXCL1, MMP3, FAP, and PDPN. In contrast, a homeostatic ADAMDEC1/TCF21-enriched fibroblast population was reduced in inflamed tissue. TCF21 expression positively correlated with ADAMDEC1 and negatively correlated with activation markers. Multiplex immunofluorescence confirmed depletion of TCF21-positive non-immune, stromal cells in IBD tissue. In vitro, IL1B and TNF induced an IAF-like phenotype and reduced TCF21. TCF21 mRNA-LNP restoration attenuated inflammatory mediators including IL1B and IL6. Conclusions: TCF21 loss identifies a conserved inflammation-associated fibroblast state across CD and UC. Restoring TCF21 partially suppresses inflammatory fibroblast programs, supporting stromal reprogramming as a therapeutic concept in IBD.