背景:干细胞疗法是炎症性疾病和组织损伤治疗的有希望的替代方法。间充质干细胞的外源性递送与即时血液介导的炎症反应有关,给药期间的机械应力,以及在体外长期培养过程中复制性衰老或表型改变。在这项研究中,我们的目的是使用AMD-3100动员内源性造血干细胞(HSC),并使用免疫抑制药物FK506提供局部免疫抑制,用于治疗炎症性肠病。
方法:通过乳化溶剂蒸发法制备了活性氧(ROS)响应性FK506负载的硫代金属微球。将基于FK506微球的硫代载体和AMD3100与葡聚糖硫酸钠(DSS)诱导的结肠炎共同给予雄性C57BL6/J小鼠。使用疾病严重程度指数评估负载FK506的硫代金属微球在结肠炎小鼠中的作用。髓过氧化物酶活性,组织学,流式细胞术,并通过qRT-PCR进行基因表达。
结果:AMD-3100的递送增强了HSC从骨髓到小鼠发炎结肠的动员。此外,在发炎的结肠中靶向口服FK506抑制了结肠中的免疫激活。在DSS诱导的结肠炎小鼠模型中,AMD-3100和FK506负载的巯基微球的组合改善了疾病,减少免疫细胞浸润和活化,和改善体重,结肠长度,和上皮愈合过程。
结论:这项研究表明,在AMD和口服FK506微球的联合治疗中,动员的造血干细胞百分比的显着增加可能有助于协同治疗作用。因此,FK506联合AMD3100的低剂量局部给药可能是炎症性肠病的有希望的替代治疗.
BACKGROUND: Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using
FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases.
METHODS: Reactive oxygen species (ROS)-responsive
FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based
FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of
FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR.
RESULTS: The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of
FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process.
CONCLUSIONS: This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.