Evelien Eenjes, Maeve L Troost, Li Lei, Alicia Köck, David Grommisch, Marin T Mondria, Kotryna Truskaite, Fredrik Klevebro, Magnus Nilsson, Maria Genander
These findings demonstrate that IL1A coordinates epithelial inflammatory and regenerative responses in the human esophagus. They further show that the outcome of IL1A signaling is determined by the surrounding inflammatory milieu, providing a framework for understanding epithelial remodeling in eosinophilic esophagitis.
BACKGROUND: The ability of barrier epithelia to sense environmental perturbations and initiate local inflammation is essential for progenitor-mediated epithelial repair and restoration of tissue integrity.
OBJECTIVE: To characterize human esophageal epithelial progenitor cell heterogeneity and identify molecular mechanisms regulating epithelial regeneration in eosinophilic esophagitis (EoE).
METHODS: Single-cell RNA sequencing of the adult human esophagus was integrated with spatial characterization of epithelial cell populations and functional analyses using primary human esophageal organoids and air-liquid interface cultures.
RESULTS: Using NGFR and P73, we defined a layer of human basal progenitor cells spanning both papillary and interpapillary regions of the human esophageal epithelium. Proliferating basal progenitor cells were enriched within the papillary epithelium, and a subset of papillary basal progenitor cells displayed active YAP signaling, revealing spatially organized heterogeneity within the progenitor compartment. NGFR-positive basal cells exhibited enhanced organoid-forming capacity and suppressed NOTCH signaling to maintain basal identity. During epithelial regeneration, IL1A was induced in primary human organoids, and an intraepithelial apical-to-basal IL1A signaling axis was identified in patients with EoE. IL1A activated NF-κB-dependent transcription, promoted basal progenitor expansion, and enhanced epithelial barrier function. Although IL13 selectively rewired IL1A-dependent transcriptional and regenerative programs, IL1A signaling remained active under inflammatory conditions.
CONCLUSION: These findings demonstrate that IL1A coordinates epithelial inflammatory and regenerative responses in the human esophagus. They further show that the outcome of IL1A signaling is determined by the surrounding inflammatory milieu, providing a framework for understanding epithelial remodeling in eosinophilic esophagitis.