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

Publication TypeJournal Article
Year of Publication2015
AuthorsGomi K, Arbelaez V, Crystal RG, Walters MS
JournalPLoS One
Date Published2015
KeywordsCell Differentiation, Cells, Cultured, Humans, Protein Structure, Tertiary, Receptor, Notch1, Receptor, Notch3, Receptors, Notch, Respiratory Mucosa, Secretory Pathway, Signal Transduction

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.

Alternate JournalPLoS ONE
PubMed ID25700162
PubMed Central IDPMC4336283
Grant ListP50HL084936 / HL / NHLBI NIH HHS / United States
R01HL107882 / HL / NHLBI NIH HHS / United States
UL1RR024143 / RR / NCRR NIH HHS / United States
UL1TR000457 / TR / NCATS NIH HHS / United States