A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma
Year: 2026
Type: preprint
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.
Authors: Tessa E Gillett, Aurore CA Gay, Jelmer R Vlasma, Alexandra B Firsova, Martin B Banchero, Anna K Renner, Amanda J Oliver, Marijn Berg, Sjors Maassen, Leonie Apperloo, Bao-Han Ly, Djoke van Gosliga, Marnix R. Jonker, Waradon Sungnak, Orestes A Carpaij, Tessa M Kole, Laura Hesse, Sharon Brouwer, Petra L van der Velde, Marissa Wisman, Akshaya K Saikumar Jayalatha, Bas G Doddema, Frederique Alleblas, Putri A Fajar, A Alexandros Imprachim, Rosalie C van Hulst, Marjan Luinge, Monique E. Lodewijk, Janna Bakker, Markus Weckmann, Corry-Anke Brandsma, Wim Timens, Judith M Vonk, Sarah A Teichmann, Christos Samakovlis, Kerstin B Meyer, Gerard H Koppelman, Maarten van den Berge, Martijn C Nawijn
Institutions: University Medical Center Groningen, University of Groningen, Stockholm University, Science for Life Laboratory, Wellcome Sanger Institute, Mahidol University, University Hospital Schleswig-Holstein, Research Center Borstel - Leibniz Lung Center, Wellcome/MRC Cambridge Stem Cell Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214214122