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1 Department of Environmental Medicine, University of Rochester, Rochester, NY, USA; Departments of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA
2 Departments of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY, USA
3 Departments of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
4 Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY, USA
5 Departments of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Departments of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: brs2{at}pitt.edu.
The composition of the conducting airway epithelium varies significantly along the proximal to distal axis, with that of the tracheal epithelium exhibiting the greatest complexity. A number of progenitor cells have been proposed to contribute to the maintenance of this cellular diversity both in the steady-state and in response to injury. However, individual roles for each progenitor cell type are poorly defined in vivo. The present study was undertaken to investigate the hypothesis that basal cells represent a multipotent progenitor cell type for renewal of the injured tracheal epithelium. GSIB4-reactive basal cells of the steady-state mouse tracheal epithelium were heterogeneous for expression of cytokeratin 14 (K14). To understand their contribution to epithelial repair mice were exposed to naphthalene to induce airway injury and depletion of the secretory cell progenitor pool. Injury resulted in a rapid induction of K14 expression among the majority of GSIB4-reactive cells and associated hyperplasia of basal cells. Restoration of depleted secretory cells occurred after 6 days of recovery and was associated with regression of the basal cell hyperplasia suggesting a progenitor-progeny relationship. Multipotent differentiation of basal cells was confirmed using a bitransgenic ligand-regulated Cre-loxP reporter approach in which expression of a ubiquitously expressed LacZ reporter was activated within K14-expressing progenitor cells during airway repair. Using this approach it was determined that K14-expressing cells include subsets capable of either multipotent or unipotent differentiation in vivo. We conclude that basal cells have the capacity for restoration of a fully differentiated epithelium.
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