Conditional Stabilization of -Catenin Expands the Pool of Lung Stem Cells

¹ Center for Lung Regeneration, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh. PA 15260
² Division of Pulmonary Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, 02115
³ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo, Kyoto 606-8501, Japan

^* To whom correspondence should be addressed. E-mail: barry.stripp{at}duke.edu.

	Abstract

Maintenance of classical stem cell hierarchies is dependent upon stem cell self-renewal mediated in part by Wnt/-catenin regulation of the cell cycle. This function is critical in rapidly renewing tissues due to the obligate role played by the tissue stem cell. However, the stem cell hierarchy responsible for maintenance of the conducting airway epithelium is distinct from classical stem hierarchies. The epithelium of conducting airways is maintained by transit-amplifying cells in the steady-state; rare bronchiolar stem cells are activated to participate in epithelial repair only following depletion of transit-amplifying cells. Here, we investigate how signaling through -catenin impacts establishment and maintenance of the stem cell hierarchy within the slowly renewing epithelium of the lung. Conditional potentiation of -catenin signaling in the embryonic lung results in amplification of airway stem cells through attenuated differentiation rather than augmented proliferation. Our data demonstrate that the differentiation modulating activities of stabilized -catenin account for expansion of tissue stem cells.