Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway

Kazunori Gomi, Vanessa Arbelaez, Ronald Crystal, Matthew S. Walters

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Airway basal cells (BC) function as stem/progenitor cells capable of differentiating into the luminal ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with γ-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secretory and ciliated cells, but more so for the secretory lineage. Sustained cell autonomous ligand independent Notch activation via lentivirus expression of the intracellular domain of each Notch receptor (NICD1-4) demonstrated that the NOTCH2 and 4 pathways have little effect on BC differentiation into secretory and ciliated cells, while activation of the NOTCH1 or 3 pathways has a major influence, with persistent expression of NICD1 or 3 resulting in a skewing toward secretory cell differentiation with a parallel decrease in ciliated cell differentiation. These observations provide insights into the control of the balance of BC differentiation into the secretory vs ciliated cell lineage, a balance that is critical for maintaining the normal function of the airway epithelium in barrier defense against the inhaled environment.

Original languageEnglish
Article numbere0116507
JournalPLoS One
Volume10
Issue number2
DOIs
Publication statusPublished - 20 Feb 2015
Externally publishedYes

Fingerprint

Secretory Pathway
cell differentiation
Cell Differentiation
Chemical activation
Cells
epithelium
Epithelium
cells
Notch Receptors
Amyloid Precursor Protein Secretases
stem cells
Stem Cells
Stem cells
Lentivirus
Repair
Cell Lineage
Ligands
receptors

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway. / Gomi, Kazunori; Arbelaez, Vanessa; Crystal, Ronald; Walters, Matthew S.

In: PLoS One, Vol. 10, No. 2, e0116507, 20.02.2015.

Research output: Contribution to journalArticle

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