Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging

Our understanding of dynamic interactions between airway basal stem cells (ABSCs) and their signaling niches in homeostasis, injury, and aging remains elusive. Using transgenic mice and pharmacologic studies, we found that Wnt/β-catenin within ABSCs was essential for proliferation post-injury in vivo. ABSC-derived Wnt ligand production was dispensable for epithelial proliferation. Instead, the PDGFRα+ lineage in the intercartilaginous zone (ICZ) niche transiently secreted Wnt ligand necessary for ABSC proliferation. Strikingly, ABSC-derived Wnt ligand later drove early progenitor differentiation to ciliated cells. We discovered additional changes in aging, as glandular-like epithelial invaginations (GLEIs) derived from ABSCs emerged exclusively in the ICZ of aged mice and contributed to airway homeostasis and repair. Further, ABSC Wnt ligand secretion was necessary for GLEI formation, and constitutive activation of β-catenin in young mice induced their formation in vivo. Collectively, these data underscore multiple spatiotemporally dynamic Wnt-secreting niches that regulate functionally distinct phases of airway regeneration and aging. [Display omitted] •Tracheal epithelial β-catenin tightly controls proliferation and differentiation•PDGFRα+ lineage comprises Wnt signaling niche necessary for epithelial proliferation•Airway basal stem cell-derived Wnts facilitate differentiation to ciliated cells•Age-related Wnt/β-catenin niche changes drive gland-like epithelial invaginations Aros et al. unveil multiple dynamic Wnt/β-catenin signaling niches that govern murine airway proliferation and differentiation. They further extend these findings in the setting of aging to elucidate how Wnt/β-catenin niche activity regulates profound structural changes in the proximal airway.