10.3389/fpsyg.2012.00132

Vollständiger Abstract

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<h4>Background</h4>Resistance to anti-TNFα therapy (e.g., infliximab) in ulcerative colitis (UC) remains a significant clinical challenge, with the underlying cellular and spatial mechanisms poorly understood.<h4>Methods</h4>We integrated bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) from clinical cohorts to systematically map the cellular landscape and identify key determinants of treatment response, followed by validation in independent clinical cohorts and <i>in vitro</i> functional experiments.<h4>Results</h4>Multi-omics cross-analysis pinpointed insulin-like growth factor-binding protein 5 (IGFBP5) as a fibroblast-specific, spatially enriched gene strongly associated with infliximab non-response. Functional analyses linked IGFBP5 to inflammatory pathways and a distinct immune-activated microenvironment. Cell-cell communication analysis revealed that IGFBP5-high fibroblasts exhibit enhanced crosstalk with monocytes, endothelial cells, and T cells via VEGF, MIF, and WNT signaling. Validation in clinical samples and functional experiments confirmed elevated expression of IGFBP5 and its downstream effectors EGR1 and VEGFR2 in non-responders, Mechanistically, IGFBP5 promoted activation of the VEGFR2/EGR1 signaling axis and enhanced the secretion of inflammatory mediators, including IL-6, CXCL12, and CCL2, thereby contributing to a pro-inflammatory fibroblast phenotype.<h4>Conclusions</h4>This study establishes fibroblast-derived IGFBP5 as a central mediator of anti-TNFα resistance in UC. The IGFBP5-EGR1-VEGFR2 axis may represent a candidate predictive biomarker and a promising target for overcoming treatment resistance.

Abstract: PubMed · Datensatz