
Wnt/β‐catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema
Author(s) -
Hu Yan,
NgBlichfeldt JohnPoul,
Ota Chiharu,
Ciminieri Chiara,
Ren Wenhua,
Hiemstra Pieter S.,
Stolk Jan,
Gosens Reinoud,
Königshoff Melanie
Publication year - 2020
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.3241
Subject(s) - wnt signaling pathway , progenitor cell , biology , organoid , microbiology and biotechnology , catenin , stem cell , pathology , signal transduction , medicine
Wnt/β‐catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/β‐catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/β‐catenin responsive progenitor cells and the potential impact of Wnt/β‐catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/β‐catenin signaling in lung organoid formation. We identified an organoid‐forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/β‐catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/β‐catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wnt low epithelial progenitors. Further ectopic Wnt/β‐catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/β‐catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase‐induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/β‐catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema.