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Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
Nature Cell Biology ( IF 17.3 ) Pub Date : 2017-07-24 00:00:00 , DOI: 10.1038/ncb3580
Ying Xi , Thomas Kim , Alexis N. Brumwell , Ian H. Driver , Ying Wei , Victor Tan , Julia R. Jackson , Jianming Xu , Dong-Kee Lee , Jeffrey E. Gotts , Michael A. Matthay , John M. Shannon , Harold A. Chapman , Andrew E. Vaughan

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.

中文翻译:

局部肺缺氧决定肺泡再生过程中的上皮命运决定

流感感染后,谱系阴性的上皮祖细胞(LNEP)对重构的上皮屏障表现出二进制反应:激活Notch依赖的ΔNp63/细胞角蛋白5(Krt5)重塑程序或分化为II型肺泡细胞(AEC2s)。在这里,我们表明,局部肺缺氧,通过低氧诱导因子(HIF1 α),驱动器Notch信号传导和KRT5 POS基底样细胞扩增。从纤维化肺中的人AEC2的单细胞转录谱分析显示缺氧亚群与激活的Notch,抑制的表面活性剂蛋白C(SPC)和向Krt5 pos基底样状态的转分化。活化鼠Krt5 posLNEP和患病的人类AEC2上调了迁移和鳞状化生的惊人相似的核心途径。而坚固,HIF1 α驱动的化生是在恢复正常的肺功能最终不如AEC2重建。HIF1 α缺失或增强的Wnt /β-catenin的活性Sox2的POS LNEPs块Notch和KRT5活化,促进,而不是快速AEC2分化和迁移并改善肺泡修复的质量。
更新日期:2017-07-30
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