Compound screening in human airway basal cells identifies Wnt pathway activators as potential pro-regenerative therapies
Year: 2025
Type: article
Abstract: ABSTRACT Regeneration of the airway epithelium restores barrier function and mucociliary clearance following lung injury and infection. The mechanisms regulating the proliferation and differentiation of tissue-resident airway basal stem cells remain incompletely understood. To identify compounds that promote human airway basal cell proliferation, we performed phenotype-based compound screening of 1429 compounds (from the ENZO and Prestwick Chemical libraries) in 384-well format using primary cells transduced with lentiviral luciferase. A total of 17 pro-proliferative compounds were validated in independent donor cell cultures, including the antiretroviral therapy agent abacavir and several Wnt signalling pathway-activating compounds. The effects of compounds on proliferation were further explored in colony formation and 3D organoid assays. Structurally and functionally related compounds that more potently induced Wnt pathway activation were investigated. One such compound, 1-azakenpaullone, induced Wnt target gene activation and basal cell proliferation in mice. Our results demonstrate the pro-proliferative effect of small-molecule Wnt pathway activators on airway basal cells. These findings contribute to the rationale to develop novel approaches to modulate Wnt signalling during airway epithelial repair.
Source: Journal of Cell Science
DOI: 10.1242/jcs.263487
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: American Association for Cancer Research, LUNGevity Foundation, Entertainment Industry Foundation, Roy Castle Lung Cancer Foundation, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Royal Society, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, University College London Hospitals NHS Foundation Trust, CRUK Lung Cancer Centre of Excellence, Johnson and Johnson, Stand Up To Cancer, Medical Research Council
Awards: G1515492571, G1647352233, UKRMP Hub: The Engineered Cell Environment., G1982650131, G2036633762, G2065746192, Delineating late foetal human lung development and maturation, G2594971299, G2733156708, The impact of mesenchymal stem cells on host immunity in bacterial lung infection and sepsis., G3194548215, G3323682383, G4360759576, G4472880597, G4719527389, G5047254407, G5165637473, G5337825365, G5359563199, G5461383728, G5520509936, G5728235598, G5890442441, G6062746524, G6158001132, G6571678050, UKDP: Integrated DEmentiA research environment (IDEA), G7423961978, G7835552818, Mapping longitudinal squamous cell lung cancer pathogenesis in pursuit of a preventative therapy, G830246384, G900861293
OpenAlex ID: W4408313102