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.

我们对气道基底干细胞 (ABSC) 及其在体内平衡、损伤和衰老中的信号通路之间的动态相互作用的理解仍然难以捉摸。使用转基因小鼠和药理学研究，我们发现 ABSCs 内的 Wnt/β-catenin 对于体内损伤后的增殖至关重要。ABSC 衍生的 Wnt 配体产生对于上皮增殖是可有可无的。相反，PDGFRα ⁺软骨间区 (ICZ) 生态位中的谱系瞬时分泌 ABSC 增殖所必需的 Wnt 配体。引人注目的是，ABSC 衍生的 Wnt 配体后来推动了早期祖细胞分化为纤毛细胞。我们发现了衰老的其他变化，因为源自 ABSC 的腺样上皮内陷 (GLEI) 仅出现在老年小鼠的 ICZ 中，并有助于气道稳态和修复。此外，ABSC Wnt 配体分泌是 GLEI 形成所必需的，年轻小鼠中 β-连环蛋白的组成型激活诱导了它们在体内的形成。总的来说，这些数据强调了多个时空动态的 Wnt 分泌壁龛，它们调节气道再生和衰老的不同功能阶段。