PI3K/Akt信号通路介导的MnSOD基因修饰的间充质干细胞对放射性肠损伤保护作用的研究

Nuclear accidents and terrorism present a serious threat for mass casualty. Accidental or intended radiation exposure leads to radiation-induced intestinal injury. However, currently there are no approved medical countermeasures for radiation-induced intestinal injury. Mesenchymal stem cells (MSCs) derived from bone marrow, a subpopulation of pluripotent stomal cell that have the ability of self-renewal, proliferate, pluripotency trans differentiation. MSCs have advantages over other stem cells in that they can be easily isolated from patients or donors, readily expanded ex vivo, and possess immunodulatory and reparative properties. Moreover, MSCs have been shown to be powerful tools in gene therapies. Thus, the therapeutic potential of MSCs has brought into the spotlights in the clinical treatment of radiation-induced intestinal injury. Manganese superoxide dismutase (MnSOD) is an important oxygen free radical scavenger in organisms. MnSOD has an effect to resist oxidative stress and tumor. In previous study, our data showed that overexpressing MnSOD showed protective effects on t-BHP induced apoptosis of MSCs. MnSOD-MSCs infusion extended the survival of mice exposed to abdominal irradiation, accelerated the recovery of radiation-induced intestine structural damage. Furthermore, the transplanted MnSOD-MSCs could colonize in the fractionated small bowel. This project will further investigate the molecular mechanisms of MnSOD-MSCs in repairing intestinal radiation injury on molecular, cellular and animal levels. The relationship between the therapeutic effects and the versatility of MnSOD-MSCs, including multilineage differentiation, anti-inflammation, anti-oxidative stress and angiogenesis promotion will also be investigated. This could provide a valuable strategy for the clinical treatment of radiation-induced intestinal injury.

放射性肠损伤常见于核事故及战时的核爆炸，也是临床腹部肿瘤放疗过程中常见的并发症，目前缺乏有效的防治手段。间充质干细胞可分泌细胞因子、免疫调节、易于外源基因转染，将其应用于放射性肠损伤的临床治疗具有广阔前景。MnSOD在机体抗炎、抗氧化及抗肿瘤中发挥重要的作用。前期研究工作表明本MnSOD过表达对t-BHP诱导产生的细胞凋亡具有保护作用。MnSOD-MSCs可提高放射性肠损伤小鼠生存率，改善小鼠一般情况及肠组织病理学损伤。本项目拟在分子、细胞和动物整体不同水平上研究MnSOD-MSCs对放射性肠损伤的修复作用机制，通过体外建立IEC-6辐射损伤模型，明确MnSOD-MSCs对小肠细胞辐射损伤的保护作用及机制；体内实验从组织修复、抗氧化应激、抗凋亡、免疫调节和抗炎症反应等方面研究MnSOD-MSCs对放射性肠损伤保护作用及机制，为放射性肠损伤的防治提供新的思路。

放射性肠损伤常见于核事故及核爆炸，也是腹部肿瘤放疗过程中的严重并发症，严重影响患者的生存与生活质量，目前仍然缺乏有效的防治手段。前期研究发现MnSOD过表达对t-BHP诱导产生的细胞凋亡具有保护作用，开展并发表了MnSOD基因修饰的间充质干细胞（MnSOD-MSCs）对急性放射性组织损伤的系列研究，结果发现MnSOD-MSCs能显著改善模型小鼠辐射敏感组织如肠、肺等组织的病理学损伤，抑制炎症反应，减少细胞凋亡，与未基因编辑的MSCs组和辐射组比较，小鼠生存率分别提高了1.3倍和1.6倍。本项目在此基础上，建立小鼠放射性肠损伤的小鼠模型，MnSOD-MSCs移植后，能显著下调血清中IL-1β、IL-6、TNF-α、TGF-β1的表达和羟脯氨酸分泌，上调抗炎症因子IL-10的表达量，结果提示MnSOD-MSCs干预具有组织修复、抗氧化应激、抗凋亡、免疫调节和抗炎症反应等作用。体外建立IEC-6细胞辐射损伤模型，探讨了MnSOD-MSCs对小肠细胞辐射氧化应激损伤和细胞凋亡保护作用的分子机制，结果提示辐射抑制PI3K/Akt通路活化，MnSOD-MSCs处理可上调PI3K的表达和Akt激酶的活化。本项目的实施为放射性肠损伤的防治作用及机制提供了全新的实验与理论依据，同时也为干细胞解决放射性器官损伤难题带来新展望。