Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair
Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair
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DOI：
10.1016/j.celrep.2020.107828
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发表时间：
2020-06-30
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：
Chen, Qian;Rehman, Jalees;Liu, Yuru
肺泡上皮由肺泡 I 型 (AT1) 和 II 型 (AT2) 细胞组成。 AT1 细胞介导气体交换，而 AT2 细胞则充当祖细胞来修复受损的肺泡。肺微血管内皮细胞（LMVEC）在调节肺泡修复中发挥着至关重要但仍知之甚少的作用。在这里，我们使用内皮特异性删除鞘氨醇激酶 1 (Sphk1)（促进 S1P 生成的关键酶）的小鼠，研究了 LMVEC 衍生的生物活性脂质 1-磷酸鞘氨醇 (SIP) 在促进肺泡修复中的作用。这些突变的肺在铜绿假单胞菌引起的肺损伤后出现了空腔扩大病变，并表现出 AT1 细胞数量减少。我们证明，LMVEC 释放的 S1P 通过其受体 S1PR2 作用于 AT2 细胞，并诱导 yes 相关蛋白 (YAP) 的核转位，YAP 是 AT2 向 AT1 转变的调节因子。因此，损伤后释放的血管分泌素S1P通过S1PR2-YAP信号轴作用于AT2细胞，促进肺泡修复所需的AT2向AT1分化。
Lung alveolar epithelium is composed of alveolar type I (AT1) and type II (AT2) cells. AT1 cells mediate gas exchange, whereas AT2 cells act as progenitor cells to repair injured alveoli. Lung microvascular endothelial cells (LMVECs) play a crucial but still poorly understood role in regulating alveolar repair. Here, we studied the role of the LMVEC-derived bioactive lipid sphingosine-1-phosphate (SIP) in promoting alveolar repair using mice with endothelial-specific deletion of sphingosine kinase 1 (Sphk1), the key enzyme promoting S1P generation. These mutant lungs developed airspace-enlargement lesions and exhibited a reduced number of AT1 cells after Pseudomonas-aeruginosa-induced lung injury. We demonstrated that S1P released by LMVECs acted via its receptor, S1PR2, on AT2 cells and induced nuclear translocation of yes-associated protein (YAP), a regulator of AT2 to AT1 transition. Thus, angiocrine S1P released after injury acts via the S1PR2-YAP signaling axis on AT2 cells to promote AT2 to AT1 differentiation required for alveolar repair.