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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 662-670

Evidence for Stem-Cell Niches in the Tracheal Epithelium

Duncan W. Borthwick, Mariam Shahbazian, Q. Todd Krantz, Julia R. Dorin, and Scott H. Randell

Medical Research Council Human Genetics Unit, Edinburgh, United Kingdom; U.S. Environmental Protection Agency, Research Triangle Park; and Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, North Carolina

It is generally important to elucidate airway epithelial cell lineages and to identify multipotent progenitors as targets for gene therapy. Stem (S) cells are typically present in specialized compartments spatially proximal to their differentiated progeny, but an equivalent paradigm has not been demonstrated in the airway. We discovered a distinct population of cells displaying high levels of keratin expression in murine tracheal submucosal gland ducts, and tested the hypothesis that bromodeoxyuridine (BrdU) label-retaining cells (LRCs), thought to represent the S-cells, were present in this compartment. Mice received weekly epithelial damage by intratracheal detergent or SO2 inhalation for 4 wk and received intraperitoneal injections of BrdU every 48 h during the injury and repair period. At 3 and 6 d after injury, BrdU-positive epithelial cells were noted along the entire tracheal length in both basal and lumenal cell positions. At later time points (20 and 95 d) LRCs were localized to gland ducts in the upper trachea and to systematically arrayed foci in the lower trachea, typically near the cartilage-intercartilage junction. LRCs were not pulmonary neuroendocrine cells. Heterotopic tracheal grafts after surface epithelial removal demonstrated reconstitution of a surface-like epithelium from gland remnants. These results suggest that airway epithelial S cells are localized to specific niches.

Abbreviations: beta -galactosidase, beta gal; bromodeoxyuridine, BrdU; calcitonin gene-related peptide, CGRP; Griffonia simplicifolia isolectin B4, GSIB4; immunoglobulin, Ig; label-retaining cell, LRC; pulmonary neuroendocrine cell, PNEC; parts per million, ppm; stem, S; transiently amplifying, TA; terminally differentiated, TD.




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