Evidence for stem-cell niches in the tracheal epithelium

It is generally important to elucidate airway epithelial cell lineages and to identify multipotent progenitors as targets for gene therapy. Stem (S) c ells are typically present in specialized compartments spatially proximal t o their differentiated progeny, but an equivalent paradigm has not been dem onstrated in the airway. We discovered a distinct population of cells displ aying high levels of keratin expression in murine tracheal submucosal gland ducts, and tested the hypothesis that bromodeoxyuridine (BrdU) label-retai ning cells (LRCs), thought to represent the S-cells, were present in this c ompartment. Mice received weekly epithelial damage by intratracheal deterge nt or SO2 inhalation for 4 wk and received intraperitoneal injections of Br dU every 48 h during the injury and repair period. At 3 and 6 d after injur y, BrdU-positive epithelial cells were noted along the entire tracheal leng th in both basal and lumenal cell positions. At later time points (20 and 9 5 d) LRCs were localized to gland ducts in the upper trachea and to systema tically arrayed foci in the lower trachea, typically near the cartilage-int ercartilage junction. LRCs were not pulmonary neuroendocrine cells, Heterot opic tracheal grafts after surface epithelial removal demonstrated reconsti tution of a surface-like epithelium from gland remnants, These results sugg est that airway epithelial S cells are localized to specific niches.