MiR-9-enriched mesenchymal stem cells derived exosomes prevent cystitis-induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice

BackgroundInflammatory response of central nervous system is an important component mechanism in the bladder pain of interstitial cystitis/bladder pain syndrome (IC/BPS). Exosomes transfer with microRNAs (miRNA) from mesenchymal stem cell (MSCs) might inhibit inflammatory injury of the central nervous system. Herein, the purpose of our study was to explore the therapeutic effects by which extracellular vesicles (EVs? derived from miR-9-edreched MSCs in IC/BPS and further investigate the potential mechanism to attenuate neuroinflammation.MethodsOn the basis of IC/BPS model, we used various techniques including bioinformatics, cell and molecular biology, and experimental zoology, to elucidate the role and molecular mechanism of TLR4 in regulating the activation of NLRP3 inflammasome in bladder pain of IC/BPS, and investigate the mechanism and feasibility of MSC-EVs enriched with miR-9 in the treatment of bladder pain of IC/BPS.ResultsThe inflammatory responses in systemic and central derived by TLR4 activation were closely related to the cystitis-induced pelvic/bladder nociception in IC/BPS model. Intrathecal injection of miR-9-enreched MSCs derived exosomes were effective in the treatment of cystitis-induced pelvic/bladder nociception by inhibiting TLR4/NF-kappa b/NLRP3 signal pathway in central nervous system of IC/BPS mice.ConclusionsThis study demonstrated that miR-9-enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis-induced bladder pain by inhibiting TLR4/NF-kappa b/NLRP3 signal pathway in interstitial cystitis mice, which is a promising strategy against cystitis-induced bladder pain. This study demonstrated that extracellular vesicles derived from miR-9-enriched mesenchymal stem cells can freely cross the blood-brain barrier into the spinal cord tissue, and then target TLR4 receptors on the activated spinal cord glial cell membrane of interstitial cystitis/bladder pain syndrome (IC/BPS) model to inhibit the activation of NLRP3 inflammatorome and release of inflammatory factors, which can reduce neuron stimulation and restore neuron firing threshold, so as to desensitize neurons and achieve the purpose of treating bladder pain in IC/BPS patients. image