较大哺乳动物的软骨气道和小鼠气管包含至少3个建立良好的干细胞区室,包括表面气道上皮(SAE)的基底细胞以及粘膜下腺(SMG)的导管和肌上皮细胞。在这里,我们证明了能够进行SAE修复的腺体Sox9表达祖细胞随着小鼠年龄的增长而下降。值得注意的是,Sox9谱系腺体祖细胞在SAE中产生基底和纤毛细胞,但不能产生分泌细胞.Lef1是腺体Sox9谱系对SAE修复的贡献所必需的,其缺失显著减少损伤后的增殖。相比之下,Sox9的体内缺失增强了损伤后不久SAE和SMG中祖细胞的增殖,但是这些祖细胞在没有Sox9的情况下无法在体外增殖,类似于先前显示的Lef1缺失。在囊性纤维化雪貂气道中,在SMG和SAE中,Sox9表达与Ki67增殖标志物表达呈负相关。使用体外和离体模型,我们证明,随着腺体祖细胞离开导管并在气道表面增殖,Sox9被消灭,并且Sox9是SMG迁移和适当分化所必需的,但不是表面气道,祖细胞。我们提出了一个模型,其中Wnt/Lef1和Sox9信号差异调节腺体祖细胞的增殖和迁移行为,分别。
Cartilaginous airways of larger mammals and the mouse trachea contain at least 3 well-established stem cell compartments, including basal cells of the surface airway epithelium (SAE) and ductal and myoepithelial cells of the submucosal glands (SMG). Here we demonstrate that glandular Sox9-expressing progenitors capable of SAE repair decline with age in mice. Notably, Sox9-lineage glandular progenitors produced basal and ciliated cells in the SAE, but failed to produce secretory cells. Lef1 was required for glandular Sox9 lineage contribution to SAE repair, and its deletion significantly reduced proliferation following injury. By contrast, in vivo deletion of Sox9 enhanced proliferation of progenitors in both the SAE and SMG shortly following injury, but these progenitors failed to proliferate in vitro in the absence of Sox9, similar to that previously shown for Lef1 deletion. In cystic fibrosis ferret airways, Sox9 expression inversely correlated with Ki67 proliferative marker expression in SMG and the SAE. Using in vitro and ex vivo models, we demonstrate that Sox9 is extinguished as glandular progenitors exit ducts and proliferate on the airway surface and that Sox9 is required for migration and proper differentiation of SMG, but not surface airway, progenitors. We propose a model whereby Wnt/Lef1 and Sox9 signals differentially regulate the proliferative and migratory behavior of glandular progenitors, respectively.