Dual-Functionalized MSCs that Express CX3CR1 and IL-25 Exhibit Enhanced Therapeutic Effects on Inflammatory Bowel Disease
Dual-Functionalized MSCs that Express CX3CR1 and IL-25 Exhibit Enhanced Therapeutic Effects on Inflammatory Bowel Disease
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表达 CX3CR1 和 IL-25 的双功能 MSC 对炎症性肠病具有增强的治疗效果。
DOI：
10.1016/j.ymthe.2020.01.020
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发表时间：
2020-04-08
影响因子：
12.4
通讯作者：
Chen, Jiangning
中科院分区：
文献类型：
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作者：
Fu, Yong;Ni, Junjun;Chen, Jiangning
间充质干细胞（MSC）在炎症性肠病（IBD）治疗中显示出巨大的希望，由于其免疫抑制能力，但其治疗效果有时会因其进入炎症结肠的低效率和体内可变的免疫调节能力而受阻。在这里，我们展示了一种新的方法来操纵MSC表达CX 3C趋化因子受体1（CX 3CR 1）和白细胞介素-25（IL-25），以促进其交付到发炎的结肠，并增强其免疫抑制能力。与未处理的MSC相比，用编码CX 3CR 1和IL-25的慢病毒（LV）感染的MSC（CX 3CR 1和IL-25-LV-MSC）表现出增强的对发炎结肠的靶向，并且在MSC静脉内注射后，在葡聚糖硫酸钠（DSS）攻击的小鼠中可以通过跨内皮迁移进一步移动到结肠组织的血管外空间。病理学指标和炎症指标显示，CX 3CR 1和IL-25 LV-MSCs的治疗效果优于未治疗MSCs。抗体阻断研究表明，双功能化MSC的增强的治疗效果依赖于CX 3CR 1和IL-25功能。总的来说，这种基于增强MSC归巢和免疫抑制能力的策略代表了一种有前途的治疗方法，可能在IBD治疗中有价值。
Mesenchymal stem cells (MSCs) have shown great promise in inflammatory bowel disease (IBD) treatment, owing to their immunosuppressive capabilities, but their therapeutic effectiveness is sometimes thwarted by their low efficiency in entering the inflamed colon and variable immunomodulatory ability in vivo. Here, we demonstrated a new methodology to manipulate MSCs to express CX3C chemokine receptor 1 (CX3CR1) and interleukin-25 (IL-25) to promote their delivery to the inflamed colon and enhance their immunosuppressive capability. Compared to MSCs without treatment, MSCs infected with a lentivirus (LV) encoding CX3CR1 and IL-25 (CX3CR1&IL-25-LV-MSCs) exhibited enhanced targeting to the inflamed colon and could further move into extravascular space of the colon tissues via trans-endothelial migration in dextran sodium sulfate (DSS)-challenged mice after MSC intravenous injection. The administration of the CX3CR1&IL-25LV-MSCs achieved a better therapeutic effect than that of the untreated MSCs, as indicated by pathological indices and inflammatory markers. Antibody-blocking studies indicated that the enhanced therapeutic effects of dual-functionalized MSCs were dependent on CX3CR1 and IL-25 function. Overall, this strategy, which is based on enhancing the homing and immunosuppressive abilities of MSCs, represents a promising therapeutic approach that may be valuable in IBD therapy.