DIk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair
DIk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair
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DOI：
10.1016/j.celrep.2019.02.046
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发表时间：
2019-03-12
期刊：
影响因子：
8.8
通讯作者：
Liu, Yuru
中科院分区：
文献类型：
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作者：
Finn, Johanna;Sottoriva, Kilian;Liu, Yuru
肺泡 I 型细胞 (AT1) 和肺泡 II 型细胞 (AT2) 调节肺泡的结构完整性和功能。 AT1 覆盖约 95% 的表面积，负责气体交换，而 AT2 具有多种功能，包括通过增殖和分化为 AT1 来修复肺泡。然而，肺泡修复的信号机制仍不清楚。在这里，我们证明，在铜绿假单胞菌诱导的小鼠急性肺损伤中，非典型Notch配体DIk1（δ样1同源物）对于AT2向AT1的分化至关重要。 Notch 信号在修复开始时在 AT2 中被激活，但随后被 DIk1 抑制。 AT2中DIk1的缺失诱导了持续的Notch激活，导致向AT1的转变停滞以及表达低水平AT1和AT2标记物的中间细胞群的积累。因此，DIk1 表达导致 Notch 信号传导精确定时抑制，并激活 AT2 向 AT1 分化，从而导致肺泡修复。
Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering similar to 95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa-induced acute lung injury in mice, that non-canonical Notch ligand DIk1 (delta-like 1 homolog) is essential for AT2-to-AT1 differentiation. Notch signaling was activated in AT2 at the onset of repair but later suppressed by DIk1 . Deletion of DIkl in AT2 induced persistent Notch activation, resulting in stalled transition to AT1 and accumulation of an intermediate cell population that expressed low levels of both AT1 and AT2 markers. Thus, DIk1 expression leads to precisely timed inhibition of Notch signaling and activates AT2-to-AT1 differentiation, leading to alveolar repair.