Myb Permits Multilineage Airway Epithelial Cell Differentiation

• Published in: Stem cells (Dayton, Ohio) Vol. 32; no. 12; pp. 3245 - 3256
• Main Authors: Pan, Jie-Hong, Adair-Kirk, Tracy L., Patel, Anand C., Huang, Tao, Yozamp, Nicholas S., Xu, Jian, Reddy, E. Premkumar, Byers, Derek E., Pierce, Richard A., Holtzman, Michael J., Brody, Steven L.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.12.2014
• Subjects: Animals; Cell differentiation; Cell Differentiation - physiology; Cell lineage; Cell Lineage - physiology; Cells; Cells, Cultured; Chronic obstructive; Chronic obstructive pulmonary disease; Cilia; Cultured; Cystic fibrosis; Epithelial Cells - metabolism; Epithelium - metabolism; Humans; Mice; Mucous membrane; Proto-Oncogene Proteins c-myb - metabolism; Pulmonary disease; Respiratory Mucosa - metabolism; Respiratory system; Respiratory System - metabolism; Secretoglobins; Stem cells; Stem Cells - cytology; Pulmonary disease; Chronic obstructive; Cell lineage; Cultured; Respiratory system; Secretoglobins; Cells; Cilia
• ISSN: 1066-5099; 1549-4918; 1549-4918
• DOI: 10.1002/stem.1814

The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one‐step program whereby a p63+ basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps are poorly defined. Here, we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb+ cells were identified as p63− and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary‐culture airway epithelial cells and Myb gene deletion in mice resulted in a p63− population with failed maturation of Foxj1+ ciliated cells as well as Scbg1a1+ and Muc5ac+ secretory cells. Consistent with these findings, analysis of whole genome expression of Myb‐deficient cells identified Myb‐dependent programs for ciliated and secretory cell differentiation. Myb+ cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63− Myb+ population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease. Stem Cells 2014;32:3245–3256