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Cell Rep. 2015 Jan 13;10(2):239-52. doi: 10.1016/j.celrep.2014.12.017. Epub 2014 Dec 31.

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

Author information

1
Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK. Electronic address: h.danahay@sussex.ac.uk.
2
Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
3
Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK.
4
Novartis Biologics Center, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
5
Discovery and Investigative Pathology, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
6
Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: aron.jaffe@novartis.com.

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.

PMID:
25558064
DOI:
10.1016/j.celrep.2014.12.017
[Indexed for MEDLINE]
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