Qian Wenwei, Wu Enhao, Chen Hong, Yao Jun, Wang Jin, Zhou Yudi, Bai Yanjin, Wang Sheng, Shen Chen, Li Yi, Zhang Yi
Department of General Surgery, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
J Crohns Colitis. 2024 Jul 13. doi: 10.1093/ecco-jcc/jjae110.
Exosome-based therapies are gaining increasing attention, with growing evidence suggesting a link between alterations in mesentery adipose tissue (MAT) and intestinal disease in Crohn's disease (CD). However, the specific mechanism by which mesenchymal stem cells (MSCs)-Exos may alleviate colitis through targeting MAT remains not fully understood.
Human umbilical cord MSCs (HucMSCs) were cultured to isolate the corresponding exosomes (HucMSCs-Exos), which were confirmed by their morphology, size distribution, and expression of markers. In vivo, 2,4,6-trinitrobenzenesulfonic acid solution (TNBS) and dextran sodium sulfate (DSS) -induced mouse colitis models were used to detect the therapeutic effects of HucMSCs-Exos. ELISA, qRT-PCR, western blotting, and immunofluorescence determined the expression of key molecules. Luciferase reporter assay was used to confirm the relationship between miR-21-5p and SPRY2.
Exosomes treatment through mesenteric injection demonstrated therapeutic effects on mesenteric inflammation and colitis. These therapeutic benefits were contingent on macrophages, significantly facilitating the M2 polarization of mesenteric macrophages. The expression data from GSE159814 and GSE211008 revealed that exosomal miR-21-5p was enriched in HucMSCs-Exos and could be delivered to macrophages. Additionally, the results indicated that miR-21-5p could directly target the 3'UTR of SPRY2 and activate the phosphorylation of ERK to modify macrophage phenotypes. Mechanistically, exosomal miR-21-5p derived from HucMSCs could promote macrophage M2 polarization via the SPRY2/ERK axis.
Mesenteric injection of HucMSCs-Exos significantly alleviates mesenteric inflammation and colitis by promoting mesenteric macrophage M2 polarization, making it a promising approach to treat colitis and suggesting therapeutic potential role of exosomal miR-21-5p in CD.
基于外泌体的疗法日益受到关注，越来越多的证据表明克罗恩病（CD）患者的肠系膜脂肪组织（MAT）改变与肠道疾病之间存在联系。然而，间充质干细胞（MSCs）来源的外泌体（Exos）通过靶向MAT减轻结肠炎的具体机制仍未完全阐明。
培养人脐带间充质干细胞（HucMSCs）以分离相应的外泌体（HucMSCs-Exos），通过形态、大小分布和标志物表达对其进行鉴定。在体内，利用2,4,6-三硝基苯磺酸溶液（TNBS）和葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型检测HucMSCs-Exos的治疗效果。采用酶联免疫吸附测定（ELISA）、定量逆转录聚合酶链反应（qRT-PCR）、蛋白质印迹法和免疫荧光法检测关键分子的表达。利用荧光素酶报告基因检测法确认miR-21-5p与SPRY2之间的关系。
通过肠系膜注射外泌体对肠系膜炎症和结肠炎具有治疗作用。这些治疗益处取决于巨噬细胞，显著促进肠系膜巨噬细胞向M2极化。来自GSE159814和GSE211008的表达数据显示，外泌体miR-21-5p在HucMSCs-Exos中富集，并可传递至巨噬细胞。此外，结果表明miR-21-5p可直接靶向SPRY2的3'非翻译区（3'UTR）并激活细胞外信号调节激酶（ERK）的磷酸化以改变巨噬细胞表型。机制上，源自HucMSCs的外泌体miR-21-5p可通过SPRY2/ERK轴促进巨噬细胞M2极化。
肠系膜注射HucMSCs-Exos可通过促进肠系膜巨噬细胞M2极化显著减轻肠系膜炎症和结肠炎，使其成为治疗结肠炎的一种有前景的方法，并提示外泌体miR-21-5p在CD中的潜在治疗作用。
