MiR‐9‐enriched mesenchymal stem cells derived exosomes prevent cystitis‐induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice
MiR‐9‐enriched mesenchymal stem cells derived exosomes prevent cystitis‐induced bladder pain via suppressing TLR4/NLRP3 pathway in interstitial cystitis mice
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DOI：
10.1002/iid3.1140
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发表时间：
2024-02-02
影响因子：
3.2
通讯作者：
Wang, Hongwei
中科院分区：
文献类型：
--
作者：
Cui, Xiangrong;Bi, Xingyu;Zhang, Xiuping;Zhang, Zhiping;Yan, Qin;Wang, Yanni;Huang, Xia;Wu, Xueqing;Jing, Xuan;Wang, Hongwei
关键词：
中枢神经系统炎症反应是间质性膀胱炎/膀胱疼痛综合征（IC/BPS）膀胱疼痛的重要组成机制。间充质干细胞（mesenchymal stem cell，MSCs）microRNA（microRNA，miRNA）介导的Exosomes转染可抑制中枢神经系统的炎症损伤。因此，我们的研究目的是探索来源于miR-9-的细胞外囊泡（EVs）对IC/BPS中MSC的治疗作用，并进一步研究其减轻神经炎症的潜在机制。在IC/BPS模型的基础上，我们运用生物信息学、细胞和分子生物学、实验动物学等多种技术手段，阐明TLR 4在调节NLRP 3炎性小体激活中的作用及其分子机制，探讨富含miR-9的MSC-EVs治疗IC/BPS膀胱疼痛的机制和可行性。在IC/BPS模型中，TLR 4激活引起的全身和中枢炎症反应与膀胱炎诱导的盆腔/膀胱伤害感受密切相关。鞘内注射miR-9-enreched MSCs来源的exosomes通过抑制IC/BPS小鼠中枢神经系统中的TLR 4/NF-κB/NLRP 3信号通路，有效治疗膀胱炎诱导的盆腔/膀胱伤害性感受。本研究表明，miR-9-enrechedMSCs来源的exosomes通过抑制间质性膀胱炎小鼠的TLR 4/NF-κB/NLRP 3信号通路减轻神经炎症和膀胱炎诱导的膀胱疼痛，这是一种有希望的对抗膀胱炎诱导的膀胱疼痛的策略。本研究证明来源于富含miR-9的间充质干细胞的细胞外囊泡可以自由穿越血脑屏障进入脊髓组织，进而靶向间质性膀胱炎/膀胱疼痛综合征（IC/BPS）模型中激活的脊髓胶质细胞膜上的TLR 4受体，抑制NLRP 3炎性组的激活和炎症因子的释放，其可以减少神经元刺激，恢复神经元放电阈值，从而使神经元脱敏，达到治疗IC/BPS患者膀胱疼痛的目的。
Inflammatory 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. On 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. The 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‑κb/NLRP3 signal pathway in central nervous system of IC/BPS mice. This study demonstrated that miR‐9‐enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis‐induced bladder pain by inhibiting TLR4/NF‑κb/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.
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