Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 5, Pages 3157-3167Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.070326
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Funding
- National Institutes of Health [GM076561, T32 HL076139]
- NHLBI [HL78145]
- Northwestern Memorial Faculty Foundation [HL071643, ES015024]
- NIEHS, NIH ONES Award [HL071643, ES013995]
- Schweppe Foundation
- American Heart Association [0530304Z]
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The Wnt/beta-catenin signaling cascade activates genes that allow cells to adopt particular identities throughout development. In adult self-renewing tissues like intestine and blood, activation of the Wnt pathway maintains a progenitor phenotype, whereas forced inhibition of this pathway promotes differentiation. In the lung alveolus, type 2 epithelial cells (AT2) have been described as progenitors for the type 1 cell (AT1), but whether AT2 progenitors use the same signaling mechanisms to control differentiation as rapidly renewing tissues is not known. Weshow that adult AT2 cells do not exhibit constitutive beta-catenin signaling in vivo, using the AXIN2(+/LacZ) reporter mouse, or after fresh isolation of an enriched population of AT2 cells. Rather, this pathway is activated in lungs subjected to bleomycin-induced injury, as well as upon placement of AT2 cells in culture. Forced inhibition of beta-catenin/T-cell factor signaling in AT2 cultures leads to increased cell death. Cells that survive show reduced migration after wounding and reduced expression of AT1 cell markers (T1 alpha and RAGE). These results suggest that AT2 cells may function as facultative progenitors, where activation of Wnt/beta-catenin signaling during lung injury promotes alveolar epithelial survival, migration, and differentiation toward an AT1-like phenotype.
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