Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury
Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury
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DOI：
10.1172/jci58097
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发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
De Langhe, Stijn P.
中科院分区：
文献类型：
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作者：
Volckaert, Thomas;Dill, Erik;De Langhe, Stijn P.
在肺发育过程中，远端间充质中的支气管旁SMC（PSMC）祖细胞分泌成纤维细胞生长因子10（Fgf 10），其作用于远端上皮祖细胞以促进其增殖。PSMC祖细胞内的β-连环蛋白信号传导对于它们的维持、增殖和Fgf 10的表达是必需的。在这里，我们报告说，这种Wnt/Fgf 10胚胎信号级联反应在萘诱导的气道上皮损伤后，在成熟的PSMCs中被重新激活。此外，我们发现，这种旁分泌Fgf 10的行动是必不可少的激活存活的变异克拉拉细胞（细胞在气道上皮细胞的替代上皮细胞起源）位于支气管肺泡管交界处和邻近的神经内分泌体。在萘损伤后，PSMCs分泌Fgf 10以激活Notch信号传导并诱导存活的变体Clara细胞中的Snail表达，其随后经历短暂的上皮向间充质转化以启动修复过程。上皮Snail表达对损伤后的再生很重要。因此，我们已经确定了PSMCs作为肺中变异Clara细胞的干细胞龛，并确定了来自龛的旁分泌Fgf 10信号传导对于萘损伤后的上皮修复至关重要。这些发现对于理解哮喘和癌症中肺修复的失调也有意义。
During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. beta-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium. Furthermore, we found that this paracrine Fgf10 action was essential for activating surviving variant Clara cells (the cells in the airway epithelium from which replacement epithelial cells originate) located at the bronchoalveolar duct junctions and adjacent to neuroendocrine bodies. After naphthalene injury, PSMCs secreted Fgf10 to activate Notch signaling and induce Snail expression in surviving variant Clara cells, which subsequently underwent a transient epithelial to mesenchymal transition to initiate the repair process. Epithelial Snail expression was important for regeneration after injury. We have therefore identified PSMCs as a stem cell niche for the variant Clara cells in the lung and established that paracrine Fgf10 signaling from the niche is critical for epithelial repair after naphthalene injury. These findings also have implications for understanding the misregulation of lung repair in asthma and cancer.