A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma
- 1University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands
Abstract
The bronchial epithelium in asthma is vulnerable to damage and has impaired barrier function, but the mechanisms by which it contributes to airway inflammation and remodelling remain unclear. Here, we dissect these epithelial and immunological disease mechanisms by establishing a comprehensive single cell atlas of the bronchial wall from 21 patients with childhood-onset asthma and 25 matched healthy controls. We identify a novel asthma-associated non-canonical epithelial differentiation trajectory in which a repair-associated KLF4+ basal cell subset differentiates into KRT13+ hillock-like cells through a proliferative KRT14+ intermediate. In vitro cultured matched primary bronchial epithelial cells show that this trajectory is retained in absence of exogenous factors. We find that IL-13 induces hillock-like cell differentiation into CEACAM5hi goblet cells, driving goblet cell metaplasia. Repair-associated basal cells and transitioning CEACAM5hi hillock-like cells strongly contribute to airway inflammation and remodelling. In turn, dendritic cells and mast cells promote a state of highly active epithelial differentiation, which shows increased multiciliated cell fate decisions, in concordance with an increase in multiciliated cell death observed in asthma. Proportions of the epithelial cells of the non-canonical differentiation trajectory are associated with clinical outcomes such as disease severity, FeNO, and small airway function.
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BibTeX
@misc{gillett2026repairassociated,
title = {{A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma}},
author = {T. E. Gillett and A. C. Gay and J. R. Vlasma and A. B. Firsova and M. B. Banchero and A. K. Renner and A. J. Oliver and M. Berg and S. Maassen and L. Apperloo and B.-H. Ly and D. van Gosliga and M. R. Jonker and W. Sungnak and O. A. Carpaij and T. M. Kole and L. Hesse and S. Brouwer and P. L. van der Velde and M. Wisman and A. K. Saikumar Jayalatha and B. G. Doddema and F. Alleblas and P. A. Fajar and A. A. Imprachim and R. C. van Hulst and M. Luinge and M. E. Lodewijk and J. Bakker and M. Weckmann and C.-A. Brandsma and W. Timens and J. M. Vonk and S. A. Teichmann and C. Samakovlis and K. B. Meyer and G. H. Koppelman and M. van den Berge and M. C. Nawijn},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752044},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752044v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma
AU - T. E. Gillett
AU - A. C. Gay
AU - J. R. Vlasma
AU - A. B. Firsova
AU - M. B. Banchero
AU - A. K. Renner
AU - A. J. Oliver
AU - M. Berg
AU - S. Maassen
AU - L. Apperloo
AU - B.-H. Ly
AU - D. van Gosliga
AU - M. R. Jonker
AU - W. Sungnak
AU - O. A. Carpaij
AU - T. M. Kole
AU - L. Hesse
AU - S. Brouwer
AU - P. L. van der Velde
AU - M. Wisman
AU - A. K. Saikumar Jayalatha
AU - B. G. Doddema
AU - F. Alleblas
AU - P. A. Fajar
AU - A. A. Imprachim
AU - R. C. van Hulst
AU - M. Luinge
AU - M. E. Lodewijk
AU - J. Bakker
AU - M. Weckmann
AU - C.-A. Brandsma
AU - W. Timens
AU - J. M. Vonk
AU - S. A. Teichmann
AU - C. Samakovlis
AU - K. B. Meyer
AU - G. H. Koppelman
AU - M. van den Berge
AU - M. C. Nawijn
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752044
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752044v1
AB - The bronchial epithelium in asthma is vulnerable to damage and has impaired barrier function, but the mechanisms by which it contributes to airway inflammation and remodelling remain unclear. Here, we dissect these epithelial and immunological disease mechanisms by establishing a comprehensive single cell atlas of the bronchial wall from 21 patients with childhood-onset asthma and 25 matched healthy controls. We identify a novel asthma-associated non-canonical epithelial differentiation trajectory in which a repair-associated KLF4+ basal cell subset differentiates into KRT13+ hillock-like cells through a proliferative KRT14+ intermediate. In vitro cultured matched primary bronchial epithelial cells show that this trajectory is retained in absence of exogenous factors. We find that IL-13 induces hillock-like cell differentiation into CEACAM5hi goblet cells, driving goblet cell metaplasia. Repair-associated basal cells and transitioning CEACAM5hi hillock-like cells strongly contribute to airway inflammation and remodelling. In turn, dendritic cells and mast cells promote a state of highly active epithelial differentiation, which shows increased multiciliated cell fate decisions, in concordance with an increase in multiciliated cell death observed in asthma. Proportions of the epithelial cells of the non-canonical differentiation trajectory are associated with clinical outcomes such as disease severity, FeNO, and small airway function.
ER -