SHED-derived exosomes ameliorate hyposalivation caused by Sjögren’s syndrome via Akt/GSK-3b/Slug-mediated ZO-1 expression  

作　　者：Zhihao Du Pan Wei Nan Jiang Liling Wu Chong Ding Guangyan Yu 

机构地区：[1]Department of Oral and Maxillofacial Surgery,Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing 100081,China [2]Department of Oral Medicine,Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing 100081,China [3]Center Laboratory,Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing 100081,China [4]Department of Physiology and Pathophysiology,Peking University School of Basic Medical Sciences,Key Laboratory of Molecular Cardiovascular Sciences,Ministry of Education,and Beijing Key Laboratory of Cardiovascular Receptors Research,Beijing 100191,China

出　　处：《Chinese Medical Journal》2023年第21期2596-2608,共13页中华医学杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(Nos.81974151 and 81771088);Peking University-Tason Stomatology Development Fund.

摘　　要：Background:Sjögren’s syndrome(SS)is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations.The treatment is still challenging.This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth(SHED-exos)in sialadenitis caused by SS.Methods:SHED-exos were administered to the submandibular glands(SMGs)of 14-week-old non-obese diabetic(NOD)mice,an animal model of the clinical phase of SS,by local injection or intraductal infusion.The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice.Protein expression was examined by western blot analysis.Exosomal microRNA(miRNAs)were identified by microarray analysis.Paracellular permeability was evaluated by transepithelial electrical resistance measurement.Results:SHED-exos were injected into the SMG of NOD mice and increased saliva secretion.The injected SHED-exos were taken up by glandular epithelial cells,and further increased paracellular permeability mediated by zonula occluden-1(ZO-1).A total of 180 exosomal miRNAs were identified from SHED-exos,and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(Akt)pathway might play an important role.SHED-exos treatment down-regulated phospho-Akt(p-Akt)/Akt,phospho-glycogen synthase kinase 3b(p-GSK-3b)/GSK-3b,and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells.Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1,a PI3K agonist.Slug bound to the ZO-1 promoter and suppressed its expression.For safer and more effective clinical application,SHED-exos were intraductally infused into the SMGs of NOD mice,and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt,p-GSK-3b/GSK-3b,and Slug and increased ZO-1 expression.Conclusion:Local application of SHED-exos in SMGs

关 键 词：Stem cells from human exfoliated deciduous teeth EXOSOMES SALIVA Sjögren’s syndrome Submandibular gland 

分 类 号：R593.2[医药卫生—内科学]