Compound screening in human airway basal cells identifies Wnt pathway activators as potential pro-regenerative therapies.

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Yuki Ishii, Jessica C Orr, Marie-Belle El Mdawar, Denise R Bairros de Pilger, David R Pearce, Kyren A Lazarus, Rebecca E Graham, Marko Z Nikolić, Robin Ketteler, Neil O Carragher, Sam M Janes, Robert E Hynds
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引用次数: 0

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 1,429 compounds (from the ENZO and Prestwick Chemical libraries) in 384-well format using primary cells transduced with lentiviral luciferase. 17 pro-proliferative compounds were validated in independent donor cell cultures, including the antiretroviral therapy 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.

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来源期刊
Journal of cell science
Journal of cell science 生物-细胞生物学
CiteScore
7.30
自引率
2.50%
发文量
393
审稿时长
1.4 months
期刊介绍: Journal of Cell Science publishes cutting-edge science, encompassing all aspects of cell biology.
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