Vagal-Alpha 7nachr Signaling Promotes Lung Stem Cells Regeneration Via Fibroblast Growth Factor 10 During Lung Injury Repair

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.