Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration.
Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration.
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ATF3定义了肺部再生必不可少的肺内皮细胞群。
DOI：
10.7554/elife.83835
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发表时间：
2023-05-26
期刊：
影响因子：
7.7
通讯作者：
Morrisey EE
中科院分区：
文献类型：
--
作者：
Niethamer TK;Levin LI;Morley MP;Babu A;Zhou S;Morrisey EE
急性损伤后，必须修复肺内的毛细血管床，以重建与外部环境的气体交换。关于驱动肺内皮细胞(EC)增殖和随后肺毛细血管再生的转录和信号因子以及它们对应激的反应，人们知之甚少。在这里，我们证明了转录因子ATF3对于流感感染后小鼠肺内皮细胞的再生反应是必不可少的。ATF3的表达定义了富含与内皮发育、分化和迁移相关的基因的毛细血管内皮细胞亚群。在肺泡再生期间，这种EC群体扩大并增加了与血管生成、血管发育和细胞应激反应相关的基因的表达。重要的是，内皮细胞特异性的ATF3缺失导致肺泡再生缺陷，部分是通过增加内皮细胞的凋亡和减少增殖来实现的。这会导致肺泡内皮细胞的全面丧失和肺泡龛的持续形态变化，包括肺气肿样表型，肺泡空间扩大，排列着缺乏血管投资的区域。综上所述，这些数据暗示ATF3是急性肺损伤血管反应的重要组成部分，而急性肺损伤是成功再生肺泡所必需的。
Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases the expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.