Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung

Henry Danahay, Angelica D. Pessotti, Julie Coote, Brooke E. Montgomery, Donghui Xia, Aaron Wilson, Haidi Yang, Zhao Wang, Luke Bevan, Chris Thomas, Stephanie Petit, Anne London, Peter LeMotte, Arno Doelemeyer, Germán L. Vélez-Reyes, Paula Bernasconi, Christy J. Fryer, Matt Edwards, Paola Capodieci, Amy ChenMarc Hild, Aron B. Jaffe

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia invitro and invivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

Original languageEnglish (US)
Pages (from-to)239-252
Number of pages14
JournalCell reports
Volume10
Issue number2
DOIs
StatePublished - Jan 13 2015

Bibliographical note

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© 2015 The Authors.

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