Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.
Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.
复制标题
DOI：
10.1038/ncb3580
复制
发表时间：
2017-08
影响因子：
21.3
通讯作者：
Vaughan AE
中科院分区：
文献类型：
--
作者：
Xi Y;Kim T;Brumwell AN;Driver IH;Wei Y;Tan V;Jackson JR;Xu J;Lee DK;Gotts JE;Matthay MA;Shannon JM;Chapman HA;Vaughan AE
流感感染后，谱系阴性上皮祖细胞（LNEPs）表现出重建上皮屏障的双重反应：激活notch依赖性ΔNp63/细胞角蛋白5 （Krt5）重塑程序或分化为肺泡II型细胞（AEC2s）。本研究表明，局部肺缺氧通过缺氧诱导因子（HIF1α）驱动Notch信号和Krt5pos基底样细胞扩增。来自纤维化肺的人类AEC2s的单细胞转录分析显示，缺氧亚群具有激活的Notch，抑制表面活性蛋白C (SPC)，并向Krt5pos基底样状态转分化。激活的小鼠Krt5pos LNEPs和患病的人类AEC2s上调了迁移和鳞状化生背后惊人相似的核心途径。hif1 α驱动的化生虽然强健，但在恢复正常肺功能方面最终不如AEC2重建。Sox2pos LNEPs中HIF1α缺失或Wnt/β-catenin活性增强会阻断Notch和Krt5的激活，而不是促进AEC2的快速分化和迁移，提高肺泡修复的质量。本文的在线版本（doi:10.1038/ncb3580）包含补充材料，仅供授权用户使用。Xi等人的研究表明，在流感感染后，缺氧会驱动Notch信号传导，使肺部的Krt5+基底样细胞扩增。HIF1α缺失时，上皮祖细胞直接分化为肺泡II型细胞，促进功能再生。本文的在线版本（doi:10.1038/ncb3580）包含补充材料，仅供授权用户使用。
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. The online version of this article (doi:10.1038/ncb3580) contains supplementary material, which is available to authorized users. Xi et al. show that after influenza infection, hypoxia drives Notch signalling to expand Krt5+ basal-like cells in the lung. On HIF1α loss, epithelial progenitors directly differentiate into alveolar type II cells and promote functional regeneration. The online version of this article (doi:10.1038/ncb3580) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
64.5
作者：
Kumar PA;Hu Y;Yamamoto Y;Hoe NB;Wei TS;Mu D;Sun Y;Joo LS;Dagher R;Zielonka EM;Wang de Y;Lim B;Chow VT;Crum CP;Xian W;McKeon F
通讯作者：
McKeon F
影响因子：
3.1
作者：
Cai Y;Yoneda M;Tomita T;Kurotani R;Okamoto M;Kido T;Abe H;Mitzner W;Guha A;Kimura S
通讯作者：
Kimura S
影响因子：
8
作者：
Dang, TP;Eichenberger, S;Carbone, DP
通讯作者：
Carbone, DP
影响因子：
64.8
作者：
Lafkas, Daniel;Shelton, Amy;Siebel, Christian W.
通讯作者：
Siebel, Christian W.
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A