Department of Pediatrics, Division of Neonatology, Will Rogers Institute Pulmonary Research Center, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Stem Cells. 2012 May;30(5):946-55. doi: 10.1002/stem.1059.
The airways of the mammalian lung are lined with highly specialized epithelial cell types that are the targets of airborne toxicants and injury. Notch signaling plays an important role in the ontogeny of airway epithelial cells, but its contributions to recruitment, expansion or differentiation of resident progenitor/stem cells, and repair and re-establishment of the normal composition of airway epithelium following injury have not been addressed. In this study, the role of a specific Notch receptor, Notch1, was investigated by targeted inactivation in the embryonic lung epithelium using the epithelial-specific Gata5-Cre driver line. Notch1-deficient mice are viable without discernible defects in pulmonary epithelial cell-fate determination and differentiation. However, in an experimental model of airway injury, activity of Notch1 is found to be required for normal repair of the airway epithelium. Absence of Notch1 reduced the ability of a population of cells distinguished by expression of PGP9.5, otherwise a marker of pulmonary neuroendocrine cells, which appears to serve as a reservoir for regeneration of Clara cells. Hairy/enhancer of split-5 (Hes5) and paired-box-containing gene 6 (Pax6) were found to be downstream targets of Notch1. Both Hes5 and Pax6 expressions were significantly increased in association with Clara cell regeneration in wild-type lungs. Ablation of Notch1 reduced Hes5 and Pax6 and inhibited airway epithelial repair. Thus, although dispensable in developmental ontogeny of airway epithelial cells, normal activity of Notch1 is required for repair of the airway epithelium. The signaling pathway by which Notch1 regulates the repair process includes stimulation of Hes5 and Pax6 gene expression.
哺乳动物肺部的气道由高度特化的上皮细胞类型组成，这些细胞是空气传播的毒素和损伤的靶标。Notch 信号通路在气道上皮细胞的发生发育中发挥着重要作用，但它在招募、扩增或分化常驻祖细胞/干细胞，以及在损伤后修复和重建正常气道上皮组成方面的作用尚未得到解决。在这项研究中，使用上皮特异性 Gata5-Cre 驱动线靶向敲除胚胎肺上皮细胞中的特定 Notch 受体 Notch1，研究了 Notch1 的作用。Notch1 缺陷小鼠在没有明显的肺上皮细胞命运决定和分化缺陷的情况下是存活的。然而，在气道损伤的实验模型中，发现 Notch1 的活性对于气道上皮的正常修复是必需的。Notch1 的缺失降低了表达 PGP9.5 的细胞群体的能力，否则 PGP9.5 是肺神经内分泌细胞的标志物，该细胞群体似乎作为 Clara 细胞再生的储备库。发现 hairy/enhancer of split-5 (Hes5) 和 paired-box-containing gene 6 (Pax6) 是 Notch1 的下游靶标。在野生型肺中，与 Clara 细胞再生相关的 Hes5 和 Pax6 表达均显著增加。Notch1 的缺失减少了 Hes5 和 Pax6，并抑制了气道上皮修复。因此，尽管 Notch1 在气道上皮细胞的发育发生中是可有可无的，但 Notch1 的正常活性对于气道上皮的修复是必需的。Notch1 调节修复过程的信号通路包括刺激 Hes5 和 Pax6 基因的表达。
