Vagal-α7nAChR signaling promotes lung stem cells regeneration via fibroblast growth factor 10 during lung injury repair
Vagal-α7nAChR signaling promotes lung stem cells regeneration via fibroblast growth factor 10 during lung injury repair
复制标题
迷走神经-α7nAChR 信号在肺损伤修复过程中通过成纤维细胞生长因子 10 促进肺干细胞再生
DOI：
10.1186/s13287-020-01757-w
复制
发表时间：
2020-06-10
影响因子：
7.5
通讯作者：
Song, Yuanlin
中科院分区：
文献类型：
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作者：
Chen, Xiaoyan;Zhao, Caiqi;Song, Yuanlin
背景肺干细胞（LSCs）的增殖和转分化可促进肺损伤的修复。肺的远端气道由迷走神经支配。迷走神经-α 7烟碱乙酰胆碱受体（α 7 nAChR）信号传导在调节肺部感染和炎症中起关键作用;然而，该途径是否可以调节LSC仍然未知。方法按已发表的方法分离和鉴定LSC（Sca 1（+）CD 45（-）CD 31（-）细胞）。用脂多糖（LPS）对α 7 nAChR敲除小鼠和野生型同窝仔进行气管内攻击以诱导肺损伤。通过颈迷走神经切断术研究迷走神经对LSC介导的肺修复的调节作用。将α 7 nAChR激动剂或成纤维细胞生长因子10（FGF 10）经气管内递送至小鼠。通过流式细胞术分析肺细胞的单细胞悬浮液。收集肺组织进行组织学、实时定量聚合酶链反应（RT-PCR）和免疫组织化学。结果体外培养的LSCs经FGF 10刺激后，仍保持多向分化能力，并转分化为肺泡Ⅱ型上皮细胞（AEC 2）。迷走神经切断术或α 7 nAChR缺乏减少了肺Ki 67（+）LSC的扩增，并阻碍了LPS诱导的肺损伤的解决。迷走神经切断术或α 7 nAChR缺乏会降低肺FGF 10的表达和AEC 2的数量。α 7 nAChR激动剂-GTS-21逆转了LPS激发的迷走神经切断小鼠中肺中FGF 10表达的减少，以及Ki 67（+）细胞、LSC、Ki 67（+）LSC和AEC 2数量的减少。补充FGF 10抵消了LPS攻击的α 7 nAChR敲除小鼠中Ki 67（+）LSC和AEC 2的损失。结论在LPS诱导的肺损伤过程中，迷走神经通过激活α 7 nAChR促进LSCs增殖和转分化，并以FGF 10依赖的方式促进肺修复。
Background Proliferation and transdifferentiation of lung stem cells (LSCs) could promote lung injury repair. The distal airways of the lung are innervated by the vagus nerve. Vagal-alpha7 nicotinic acetylcholine receptor (alpha 7nAChR) signaling plays a key role in regulating lung infection and inflammation; however, whether this pathway could regulate LSCs remains unknown. Methods LSCs (Sca1(+)CD45(-)CD31(-)cells) were isolated and characterized according to a previously published protocol. alpha 7nAChR knockout mice and wild-type littermates were intratracheally challenged with lipopolysaccharide (LPS) to induce lung injury. A cervical vagotomy was performed to study the regulatory effect of the vagus nerve on LSCs-mediated lung repair. alpha 7nAChR agonist or fibroblast growth factor 10 (FGF10) was intratracheally delivered to mice. A single-cell suspension of lung cells was analyzed by flow cytometry. Lung tissues were collected for histology, quantitative real-time polymerase chain reaction (RT-PCR), and immunohistochemistry. Results We found that LSCs maintained multilineage differentiation ability and transdifferentiated into alveolar epithelial type II cells (AEC2) following FGF10 stimulation in vitro. Vagotomy or alpha 7nAChR deficiency reduced lung Ki67(+)LSCs expansion and hampered the resolution of LPS-induced lung injury. Vagotomy or alpha 7nAChR deficiency decreased lung FGF10 expression and the number of AEC2. The alpha 7nAChR agonist-GTS-21 reversed the reduction of FGF10 expression in the lungs, as well as the number of Ki67(+)cells, LSCs, Ki67(+)LSCs, and AEC2 in LPS-challenged vagotomized mice. Supplementation with FGF10 counteracted the loss of Ki67(+)LSCs and AEC2 in LPS-challenged alpha 7nAChR knockout mice. Conclusions The vagus nerve deploys alpha 7nAChR to enhance LSCs proliferation and transdifferentiation and promote lung repair in an FGF10-dependent manner during LPS-induced lung injury.