Beta-catenin/T-cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells.
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. We show 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 (T1alpha 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.
Flozak
Annette S
AS
Department of Medicine, Division of Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Lam
Anna P
AP
Russell
Susan
S
Jain
Manu
M
Peled
Ofra N
ON
Sheppard
Kerry A
KA
Beri
Rohinee
R
Mutlu
Gökhan M
GM
Budinger
G R Scott
GR
Gottardi
Cara J
CJ
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism*; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051820:TCF Transcription Factors; D051176:beta Catenin; D001761:Bleomycin