Wnt/β‐catenin signaling is critical for regenerative potential of distal lung epithelial progenitor cells in homeostasis and emphysema

• Published in: Stem cells (Dayton, Ohio) Ohio), 2020-11, Vol.38 (11), p.1467-1478
• Main Authors: Hu, Yan, Ng‐Blichfeldt, John‐Poul, Ota, Chiharu, Ciminieri, Chiara, Ren, Wenhua, Hiemstra, Pieter S., Stolk, Jan, Gosens, Reinoud, Königshoff, Melanie
• Format: Article
• Language: English
• Subjects: Alveoli; Animals; beta Catenin - metabolism; Catenin; Cell activation; Cell fate; Cell proliferation; Cells (biology); chronic lung disease; Elastase; Emphysema; Emphysema - genetics; Emphysema - pathology; Epithelial cells; Homeostasis; Homeostasis - physiology; Humans; LEF protein; Lung diseases; lung epithelial progenitor; Mice; organoid; Organoids; Progenitor cells; regeneration; Signaling; Stem cells; Stem Cells - metabolism; Wnt protein; Wnt Signaling Pathway; Wnt/β‐catenin
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3241

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 Wntlow 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. Wnt/β‐catenin signaling supports alveolar, bronchiolar, and bronchioalveolar organoids formation from distal lung epithelial progenitors of healthy lungs. In emphysema, a chronic lung disease characterized by distal tissue destruction and reduction of Wnt/β‐catenin activity, distal lung epithelial progenitors are impaired and form fewer alveolar organoids. Activation of Wnt/β‐catenin signaling rescues alveolar organoid formation, thus revealing a novel mechanism of lung epithelial progenitor cell activation in emphysema.