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

Abstract

Maintenance of classic 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 classic stem cell 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 affects 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. STEM CELLS

Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion

“…Alternatively, BASCs may play a role in lung development, and the requirement for Bmi1 function may not occur in these cells until they have undergone a threshold of proliferative rounds (28). Supporting the former, we and others have identified BASCs in adult lung but not during lung development (C. Kim, unpublished data) (29). We favor the hypothesis that BASCs function specifically in response to lung insults in adults.…”

Characterization of the cell of origin for small cell lung cancer

“…28,29 The same conditional allele of p53 and a different conditional allele of Rb 48 were bred together and crossed to Scgb1a1-Cre mice. [19][20][21] The two reporter mouse strains used, Rosa26R and Rosa26 LSL-YFP/+ , have been extensively described in reference 23 and 26. Doxycycline was administered in the drinking water at 1 mg/ml for one month as previously described in references 28 and 29.…”

“…Because most of the SCLC lesions are found in bronchioles and terminal bronchioles, which are composed in majority of Clara cells, we crossed Rb lox/lox ;p53 loxlox mice to Scgb1a1-Cre mice. [19][20][21] Scgb1a1 codes for the Clara cell-specific protein (CCSP, also known as CCA or CC10), which marks Clara cells throughout the distal bronchiolar epithelium as well as BASCs at the BADJ 15,22 and Cre expression in the Scgb1a1-Cre strain, has been shown to be limited to the bronchiolar epithelium. [19][20][21] To confirm these previous reports, we crossed Scgb1a1-Cre mice to Rosa26 lox-stop-lox-LacZ (Rosa26R) reporter mice, where lacZ expression is induced after Cre-mediated recombination, 23 and detected lacZ activity by X-gal staining in the bronchiolar epithelium but not in neuroendocrine cells, as expected (Fig.…”

Airway epithelial cell differentiation during lung organogenesis requires C/EBPα and C/EBPβ

“…8). In addition, Notch signaling has been suggested to promote differentiation of epithelial precursors toward the Clara cell lineage, at the expense of ciliated cells (Morimoto et al, 2010), and Wnt/b-catenin signaling has been suggested to be important to define the distal airway epithelium and to inhibit differentiation of brochiolar stem cells (Mucenski et al, 2003;Reynolds et al, 2008 (Sugahara et al, 2001). To investigate the consequence of added C/EBPb deletion in C/EBPa-deficient mice, immunodetection of pro-surfactant protein-C (SP-C), a marker for type II pneumocytes (Sugahara et al, 2001), was performed ( Fig.…”