Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation

• Published in: Cell reports (Cambridge) Vol. 17; no. 9; pp. 2312 - 2325
• Main Authors: Frank, David B., Peng, Tien, Zepp, Jarod A., Snitow, Melinda, Vincent, Tiffaney L., Penkala, Ian J., Cui, Zheng, Herriges, Michael J., Morley, Michael P., Zhou, Su, Lu, Min Min, Morrisey, Edward E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.11.2016
• Subjects: alveolus; Animals; Axin Protein - metabolism; Cell Differentiation; cell fate; Cell Lineage; Cell Proliferation; Cell Self Renewal; Clone Cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelium - embryology; Genes, Reporter; Integrases - metabolism; lung; Lung - embryology; Mice; Models, Biological; Organogenesis - genetics; Organoids; Pulmonary Alveoli - cytology; Pulmonary Alveoli - embryology; Wnt; Wnt Signaling Pathway - genetics; lung; Wnt; cell fate; alveolus
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.001

Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2. The number of AT2Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in vivo clonal analysis, and ex vivo lung organoid assays reveal that AT2sAxin2 promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation. [Display omitted] •An Axin2+ AT2 cell (AT2Axin2) promotes lung alveolar growth•Wnt signaling expands the AT2Axin2 sublineage•Inhibition of Wnt signaling shunts the AT2Axin2 sublineage into the AT1 lineage Frank et al. demonstrate that Wnt-responsive AT2 cells play a critical role in lung alveologenesis. Wnt signaling promotes Axin2+ AT2 cell growth while inhibiting their differentiation into the AT1 lineage, revealing a balance between these two processes regulated by a wave of Wnt signaling during lung alveologenesis.