Research progress on mesenchymal stem cell products and their exosomes in the treatment of inflammatory bowel disease
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摘要:
炎症性肠病（inflammatory bowel disease, IBD）发病机制不明，特征为进行性和终身复发性消化道炎症反应。尽管现阶段新的治疗药物和策略不断涌现，但治疗作用局限于单一的抗炎功能，在复杂黏膜免疫环境下易出现耐药导致治疗失败。间充质干细胞（mesenchymal stem cells, MSCs）能定向归巢到结肠炎症部位，具有强大的免疫调节能力，可重塑肠道免疫环境和修复上皮屏障，为药物难治性患者的治疗提供了极具潜力的替代方案。本文对MSCs产品及其衍生的外泌体在临床上的应用、作用机制和工程化进行综述，以期为MSCs及其外泌体产品用于IBD的治疗提供参考。
Abstract:Inflammatory bowel disease (IBD), whose pathogenesis remains elusive, is a group of autoimmune diseases characterized by chronic, progressive, and lifelong inflammation of the digestive tract. The pathogenesis of IBD remains elusive. Although a number of drugs have been developed to treat IBD, their effects are merely anti-inflammatory. In addition, current treatments for IBD are easily susceptible to resistance in clinical practice. Mesenchymal stem cells (MSCs) have been reported to have the ability to migrate to the site of inflammation, with potent immunoregulatory effects, and to rebalance the immune microenvironment and restore the integrity of the epithelial barrier with significant value of application, particularly for patients who are refractory to classic medicines. In this paper, we reviewed the clinical applications, mechanisms and engineerable properties of MSC products and their exosomes to provide some reference for the use of MSCs and their exosomes in the treatment of IBD.
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Keywords:
- inflammatory bowel disease /
- mesenchymal stem cells /
- exosomes /
- engineering
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图 1 MSCs用于难治性炎症性肠病（IBD）治疗的优势示意图
A：在难治性IBD患者的肠壁损伤部位，炎性巨噬细胞可释放多种细胞因子，加重局部免疫微环境的失调；B：MSCs对于应用抗体类生物药物或传统药物无效的IBD患者具有治疗效果；C：MSCs在pfCD患者中的应用：瘘管部位CD68+巨噬细胞、CD45RO+ T细胞和CD20+ B细胞密集浸润，释放很多TNF-α、IFN-γ、IL-6和IL-17，MSCs可对瘘管的局部炎症微环境做出响应，发挥免疫调节及瘘管修复作用OSM：抑瘤素-M；IFN-γ：干扰素-γ；pfCD：肛周瘘管性克罗恩病
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图 2 MSCs治疗IBD的机制和特征
A：MSCs能与各种免疫细胞如巨噬细胞、T细胞和中性粒细胞相互作用，抑制炎症；B：给药后，MSCs可以迁移到炎症部位，MSCs的定向迁移受到多种因子的驱动，如MMP、P-选择素和CXCR4-CXCL12轴；C：MSCs分泌VEGF促进血管生成；D：通过分泌TSG-6和IGF-1，MSCs促进上皮细胞增殖，增强肠道屏障完整性；E：MSCs对肠道神经元的保护作用；F：MSC-Exos含有miR-200b能够逆转IBD结肠纤维化TSG-6：肿瘤坏死因子刺激基因-6；IGF-1：胰岛素样生长因子-1；MMP：基质金属蛋白酶；VEGF：血管内皮生长因子；CXCR：C-X-C趋化因子受体; CXCL：C-X-C趋化因子配体；MSC-Exos：由MSCs产生的外泌体（exosomes）
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图 3 MSCs 及MSC-Exos 的工程化
A：过表达CXCR2、CXCR4、CX3CR1和ICAM-1的MSCs表现出对结肠的增强的定向迁移；B：多价VCAM-1抗体修饰的MSCs显示对炎症性内皮细胞的增强黏附，提高了对炎症部位的归巢；C：负载于生物材料支架上的MSCs减轻局部炎症并促进再生；D：过表达miR-146a的MSC-Exos具有更强的抗炎效果；E：MSC-Exos包裹在海藻酸钠微球中，微球被明胶层和pH敏感的Eudragit FS30D丙烯酸树脂壳包裹，可保护MSC-Exos免受降解AAV：腺相关病毒；CX3CR：C-X3-C趋化因子受体；ICAM-1：细胞间黏附分子-1；VCAM-1：血管细胞黏附分子-1；NF-κB：核因子-κB
表 1 已上市用于炎症性肠病治疗的药物与间充质干细胞（MSCs）产品的对比
分类 代表药物 作用机制 适应证 给药方式 剂量 不良反应 氨基水杨酸类 美沙拉嗪 抑制免疫细胞的免疫反应
和促炎因子产生轻、中度UC和轻度CD诱导和维持缓解 po 2 ~ 4 g/d分次口服或顿服 磺胺过敏、胃肠道反应、肝肾功能损害和胰腺炎 糖皮质激素 泼尼松龙 抑制炎症因子转录，促进炎症细胞凋亡 UC&CD 不用于维持治疗 po
iv
im活动期每日0.75~
1 mg/kg, t.i.d.青光眼、高血糖症、高血压和库欣综合征等 抗TNF-α 英夫利昔单抗 抑制TNF-α信号转导通路 UC&CD iv 5 mg/kg，0, 2, 6 w给药，随后每 8周给药 严重感染、恶性肿瘤、银屑病等 抗IL-12/IL-23 乌司奴单抗 与IL-12p40结合，阻断IL-12 / IL-23通路 UC&CD iv
s.c.45 mg，0, 4 w给药，随后每12 周给药 感染、恶性肿瘤、过敏反应 抗整合素 维得利珠单抗 抑制白细胞归巢 UC&CD iv 300 mg，0, 2, 6 w给药，随后每8周给药 严重感染、过敏反应、多灶性脑白质病 免疫调节剂 6-巯基嘌呤 破坏嘌呤代谢 UC&CD po 每日1.5~2.5 mg/kg, b.i.d., t.i.d. 骨髓抑制、肝功能损害、恶心、呕吐 JAK 抑制剂 托法替尼 阻断JAK介导的细胞因子信号通路 UC&CD po 5~10 mg, b.i.d. 头晕、头痛、胃肠反应、感染 S1P 受体调节剂 奥扎莫德 抑制淋巴细胞归巢 UC po 开始治疗需滴定 维持：0.92 mg, q.d. 上呼吸道感染、头痛 MSCs Darvadstrocel 免疫抑制、组织修复、抗纤维化、保护神经元 CD合并复杂性肛瘘 瘘管内
注射每千克1×106 ~2×106个细胞，长期有效 暂无不良反应事件报告 Cupistem UC：溃疡性结肠炎；CD：克罗恩病；IL：白介素； TNF-α：肿瘤坏死因子-α；JAK：Janus激酶；S1P：鞘氨醇-1-磷酸 
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