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

Abstract

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.

Inhalable textile microplastic fibers impair lung repair

“…In addition, this also gave us the opportunity to directly study human lung epithelial repair, showing us these effects of microplastic textile fibers are relevant for human epithelial differentiation and growth too. Despite these strengths (32,33,58,72,73), lung organoids are a relatively simple model of lung tissue and lack the immune and endothelial compartment present in vivo. Especially having the immune compartment present could alter how lung tissue responds to these microplastic fibers.…”

Lung organoids, useful tools for investigating epithelial repair after lung injury

“…Recently, another team identified a population of adult distal lung epithelial progenitor cells with low Wnt/β-catenin activity. Their strong organoid-forming capacity means that they play an important role in the alveolar epithelial repair [ 61 ]. Moreover, 3D-ALI has been employed to study lineage-negative epithelial progenitors; these are another type of distal airway progenitor cells that differentiate into AT2 cells and rebuild the epithelium after epithelial damage [ 62 ].…”

Lung regeneration: implications of the diseased niche and ageing

“…In the alveolar region, the main progenitor cells (AT2 cells) become senescent in older mice, losing their progenitor capacity [40]. Under physiological conditions, the Wnt signalling pathway is required for AT2 progenitor cell function and tissue homeostasis [40,41], while aberrantly activated Wnt/β-catenin signalling in AT2 cells has been related to IPF pathogenesis and cellular senescence [40,42]. Moreover, AT2 cells in older mice exhibit higher Nrf2-mediated oxidative stress responses and mammalian target of rapamycin (mTOR) activity [43].…”

“…However, murine alveolar organoids have been very useful to study age-related changes [40,63,136] and how they impair progenitor cell potential and epithelial-mesenchymal crosstalk [137]. Recently, organoid assays led to the discovery of a murine epithelial progenitor population that requires low Wnt/β-catenin signalling, which is impaired in emphysema [41]. Likewise, transient inhibition of the retinoic acid pathway followed by histone deacetylase inhibition was identified as a potential therapeutic option for regenerative treatments [138].…”