HucMSC调控巨噬细胞15-LOX-1表达促进炎症性肠病修复的机制研究

Many attentions have been paid to mesenchymal stem cell (MSC) transplantation in inflammatory bowel disease (IBD) treatment. Macrophages are involved in MSC-mediated inflammatory disease treatment, while the mechanism of the involvement of 15-lipoxygenase-1 (15-LOX-1) in IBD treatment by macrophage mediated human umbilical cord MSC (hucMSC) remains unclear. We have found that transplantation of hucMSC was an effective strategy in IBD treatment induced by dextran sulfate sodium (DSS) in mice with a decrease of 15-LOX-1 expression. In addition, hucMSC can down-regulate the 15-LOX-1 expression in macrophage in vitro. In this proposal, firstly we are going to establish the model of hucMSC transplantation in DSS-induced IBD mice and ascertain the treatment effect of hucMSC through regulating macrophage. And then the molecular mechanisms of the 15-LOX-1 down-regulation in macrophage mediated by hucMSC will be investigated by luminex and signal pathway chip analysis. Furthermore, we will explore the function of 15-LOX-1 during the treatment of IBD by macrophage-mediated hucMSC. The proposed research could provide new experimental evidence for the treatment of IBD by hucMSC in clinic, which has important research significance and clinical application value.

间质干细胞（MSC）移植治疗炎症性肠病（IBD）已经引起人们的重视。巨噬细胞是MSC移植治疗炎症损伤性疾病的重要参与者，但MSC是否通过调控巨噬细胞15-脂氧合酶-1(15-LOX-1）的表达来治疗IBD尚不清楚。我们发现人脐带MSC有效治疗DSS诱导的小鼠IBD，并伴随15-LOX-1的表达降低且人脐带MSC在体外下调巨噬细胞表达15-LOX-1。本课题拟建立人脐带MSC（hucMSC）治疗DSS诱导的小鼠IBD模型，明确人脐带MSC调控巨噬细胞治疗IBD的作用；采用Luminex及信号通路芯片分析等技术阐明人脐带MSC下调巨噬细胞表达15-LOX-1的分子机制，探讨15-LOX-1在巨噬细胞介导人脐带MSC治疗IBD中的作用，为临床应用人脐带MSC治疗IBD提供新的实验依据，具有重要的研究意义和应用价值。

炎症性肠病（IBD）是一组由环境、遗传、感染以及免疫等因素相互作用而导致的肠道黏膜免疫系统异常反应的疾病。IBD因其发病率不断升高、难以彻底治愈且长期迁延不愈易诱发肿瘤等特点，已成为国际消化学界研究的热点和难点之一，目前仍缺乏有效治疗策略。近年来的研究显示间质干细胞（MSCs）在局部移植、系统移植、组织工程以及组织损伤修复等领域具有非常好的应用前景。本课题旨在寻找新的治疗IBD的策略并探讨其作用机制。该研究通过人脐带间质干细胞（hucMSCs）处理DSS诱导的IBD模型的建立，揭示了hucMSCs对DSS诱导的IBD的修复作用机制。我们采用hucMSCs处理DSS诱导的IBD模型研究hucMSCs对DSS诱导的IBD的治疗作用，研究结果表明hucMSCs具有修复DSS诱导的IBD的作用，其机制可能是由于hucMSCs及其分泌的exosome下调巨噬细胞表达15-LOX-1以及IL-7等细胞因子的表达水平导致。进一步的研究结果显示hucMSCs分泌的miR148b-5p通过下调巨噬细胞中15-LOX-1的表达来缓解IBD。此外，我们在研究中还发现：hucMSCs通过调控中性粒细胞ERK的磷酸化水平缓解IBD；hucMSCs来源的exosome (hucMSC-Ex)通过调控NLRP3炎症小体的形成及抑制neddylation缓解DSS诱导的小鼠IBD等。综上所述，本课题阐明了hucMSCs修复IBD的作用及其机制，为临床应用hucMSCs治疗IBD提供实验依据，具有重要的研究价值和社会意义。