生物
炎症
细胞生物学
鼻息肉
干细胞
免疫学
细胞分化
生物化学
基因
作者
Xin Wang,Nils Hallen,Min-Kyu Lee,Sachin K. Samuchiwal,Qihua Ye,Kathleen M. Buchheit,Alice Z. Maxfield,Rachel E. Roditi,Regan W. Bergmark,Neil Bhattacharyya,Tessa Ryan,Deb Gakpo,Soumya Raychaudhuri,Dan Dwyer,Tanya M. Laidlaw,Joshua A. Boyce,María Gutiérrez‐Arcelus,Nora A. Barrett
标识
DOI:10.1016/j.jaci.2023.01.030
摘要
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal cells (BCs). Recent studies have identified transcriptionally distinct BCs, but the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown.We sought to determine the role of T2 cytokines in regulating airway BCs.Single-cell and bulk RNA sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of inhibitors of IL-4R signaling. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and regeneration.Two subsets of BCs were found in human and murine respiratory mucosa distinguished by the expression of basal cell adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhi BCs expressing TSLP, IL33, CCL26, and the canonical BC transcription factor TP63 are increased in patients with CRSwNP. In cultured BCs, IL-4/IL-13 increases the expression of BCAM and TP63 through an insulin receptor substrate-dependent signaling pathway that is increased in CRSwNP.These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.
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