JAG1 Mediated Notch Signaling Regulates Secretory Cell Differentiation of the Human Airway Epithelium

Background: Basal cells (BC) are the stem/progenitor cells of the human airway epithelium capable of differentiating into secretory and ciliated cells. Notch signaling activation increases BC differentiation into secretory cells, but the role of individual Notch ligands in regulating this process is unknown Results: The objective of this study was to define the role of the Notch ligand JAG1 in regulating BC differentiation. JAG1 over-expression in BC increased secretory cell differentiation, with no effect on ciliated cell differentiation. Conversely, knockdown of JAG1 decreased expression of secretory cell genes. Conclusions: These data demonstrate JAG1 mediated Notch signaling regulates differentiation of BC into secretory cells. This study demonstrates that expression of the Notch ligand JAG1 is highly enriched in basal stem/progenitor cells (BC) of the human airway epithelium and that modulation of its expression levels during differentiation of BC play an important role in regulating secretory cell differentiation with no effect on ciliated cell differentiation. These observations have implications for developing novel targets to specifically modulate levels of secretory cells in human airway disorders. Overall design: RNA sequencing of primary (Passage 0) and immortalized BC was performed on cells once they had reached 70-80% confluence. The 8 RNA-Seq samples in this submission were all normal, nonsmoker samples without any over-expression or knock-down. The 8 RNA-Seq samples show the BCiNS1.1 cell line samples to be similar to the primary basal cell (BC) samples.

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Gomi K, Staudt MR, Salit J, Kaner RJ, Heldrich J, Rogalski AM, Arbelaez V, Crystal RG, Walters MS