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Tissue-Specific Stem Cells
Article first published online: 9 APR 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 5, pages 946–955, May 2012
How to Cite
Xing, Y., Li, A., Borok, Z., Li, C. and Minoo, P. (2012), NOTCH1 Is Required for Regeneration of Clara Cells During Repair of Airway Injury. STEM CELLS, 30: 946–955. doi: 10.1002/stem.1059
Author contributions: Y.X.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; A.L.: collection and/or assembly of data; Z.B.: data analysis and interpretation and manuscript writing; C.L.: data analysis and interpretation; P.M.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS February 13, 2012.
- Issue published online: 9 APR 2012
- Article first published online: 9 APR 2012
- Accepted manuscript online: 13 FEB 2012 04:41PM EST
- Manuscript Accepted: 23 JAN 2012
- Manuscript Received: 14 NOV 2011
- Hastings Foundation
- Lung morphogenesis;
- Epithelial repair;
- Clara cells;
- Pulmonary neuroendocrine;
- Stem cells;
- Progenitor cells;
- Cell fate
The airways of the mammalian lung are lined with highly specialized epithelial cell types that are the targets of airborne toxicants and injury. Notch signaling plays an important role in the ontogeny of airway epithelial cells, but its contributions to recruitment, expansion or differentiation of resident progenitor/stem cells, and repair and re-establishment of the normal composition of airway epithelium following injury have not been addressed. In this study, the role of a specific Notch receptor, Notch1, was investigated by targeted inactivation in the embryonic lung epithelium using the epithelial-specific Gata5-Cre driver line. Notch1-deficient mice are viable without discernible defects in pulmonary epithelial cell-fate determination and differentiation. However, in an experimental model of airway injury, activity of Notch1 is found to be required for normal repair of the airway epithelium. Absence of Notch1 reduced the ability of a population of cells distinguished by expression of PGP9.5, otherwise a marker of pulmonary neuroendocrine cells, which appears to serve as a reservoir for regeneration of Clara cells. Hairy/enhancer of split-5 (Hes5) and paired-box-containing gene 6 (Pax6) were found to be downstream targets of Notch1. Both Hes5 and Pax6 expressions were significantly increased in association with Clara cell regeneration in wild-type lungs. Ablation of Notch1 reduced Hes5 and Pax6 and inhibited airway epithelial repair. Thus, although dispensable in developmental ontogeny of airway epithelial cells, normal activity of Notch1 is required for repair of the airway epithelium. The signaling pathway by which Notch1 regulates the repair process includes stimulation of Hes5 and Pax6 gene expression. STEM CELLS 2012;30:946–955