Allergic inflammatory memory in human respiratory epithelial progenitor cells.

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Barrier tissue dysfunction is central to chronic inflammatory diseases.
• Upper airway protection relies on specialized epithelial cells differentiating from basal stem cells.
• Allergic inflammation, specifically type 2 immunity, drives chronic rhinosinusitis, from rhinitis to nasal polyps, with basal cell hyperplasia as a severe disease marker.

Purpose of the Study:

• To investigate the role of basal progenitor cells in chronic rhinosinusitis and barrier tissue dysfunction.
• To profile cell types and subsets in human chronic rhinosinusitis, focusing on type 2 inflammation.
• To identify molecular mechanisms underlying polyp formation and persistence.

Main Methods:

• Massively parallel single-cell RNA sequencing (Seq-Well) of 18,036 cells from human surgical chronic rhinosinusitis samples (n=12).
• Comparative analysis with 18,704 cells from nasal scrapings (n=9) to define healthy, inflamed, and polyp cell signatures.
• Functional assays of ex vivo cultured basal cells and in vivo testing of IL-4 receptor alpha-subunit blockade.

Main Results:

• Significant differences in epithelial compartments between non-polyp and polyp tissues, revealing reduced cellular diversity in polyps.
• Polyps exhibit basal cell hyperplasia, decreased glandular cells, and altered secretory cell antimicrobial expression.
• Aberrant basal progenitor differentiation trajectory in polyps, linked to cell-intrinsic, epigenetic, and extrinsic factors; basal cells retain IL-4/IL-13 exposure memory.

Conclusions:

• Reduced epithelial diversity, driven by functional shifts in basal cells, characterizes type 2 immune-mediated barrier tissue dysfunction.
• Epithelial stem cells may perpetuate chronic rhinosinusitis by storing allergic memories.
• Targeting the IL-4 receptor pathway offers potential therapeutic strategies for modifying airway epithelial cell states in vivo.