title: Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung.
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.
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK. Electronic address: h.danahay@sussex.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Danahay
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Angelica D
authors.initials: AD
authors.lastname: Pessotti
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Coote
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Montgomery
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Donghui
authors.initials: D
authors.lastname: Xia
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Haidi
authors.initials: H
authors.lastname: Yang
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Bevan
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Petit
authors.affiliation: Novartis Biologics Center, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: London
authors.affiliation: Novartis Biologics Center, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: LeMotte
authors.affiliation: Discovery and Investigative Pathology, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Arno
authors.initials: A
authors.lastname: Doelemeyer
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Germán L
authors.initials: GL
authors.lastname: Vélez-Reyes
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Bernasconi
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Fryer
authors.affiliation: Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK.
authors.forename: Matt
authors.initials: M
authors.lastname: Edwards
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Capodieci
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Chen
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: aron.jaffe@novartis.com.
authors.forename: Aron B
authors.initials: AB
authors.lastname: Jaffe
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D055257:Mucin-5B / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology
chemical_list: D016207:Cytokines; C496505:FOXA3 protein, human; D018793:Interleukin-13; D020381:Interleukin-17; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; C497764:NOTCH2 protein, human; D051883:Receptor, Notch2; D011994:Recombinant Proteins; D051543:Hepatocyte Nuclear Factor 3-gamma