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

Hu, Y., Ng-Blichfeldt, J-P., Ota, C., Ciminieri, C., Ren, W., Hiemstra, P. S., Stolk, J., Gosens, R. & Königshoff, M., 11-Jun-2020, In : STEM CELLS.

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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 a TCF: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. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: The field of regenerative lung biology lacks understanding of mechanisms regulating lung progenitor behavior in homeostasis and in chronic diseases. Our study demonstrate a distinct, broad, Wnt-responsive cellular landscape in the lung ex vivo and in vivo. We reveal nuances in Wnt signaling dynamics during organoid formation that have not previously been described. Importantly, we utilized an elastase induced mouse emphysema model to show for the first time that distal lung epithelial progenitor cell function is impaired in a chronic lung disease. We strongly believe that our study will advance the field, contributing to our understanding of how lung repair and regeneration upon chronic lung injury is controlled in distinct cell populations and thus will potentially aid the rational design of cell-specific therapeutics aimed at inducing lung regeneration in lung diseases, which represent the second leading causes of death worldwide.

Original languageEnglish
Publication statusE-pub ahead of print - 11-Jun-2020

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