Danahay, Henry, Pessotti, Angelica, Coote, Julie, Montgomery, Brooke, Xia, Donghui, Wilson, Aaron, Yang, Haidi, Wang, Zhao, Bevan, Luke, Thomas, Chris, Petit, Stephanie, London, Anne, Lemotte, Peter, Doelemeyer, Arno, Velez-Reyes, German, Bernasconi, Paula, Fryer, Christy, Edwards, Matthew, Capodieci, Paola, Chen, Amy, Hild, Marc and Jaffe, Aron (2015) Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung. Cell Reports.

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 in vitro and in vivo. 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.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9894