Trx协同骨髓间充质干细胞对早产鼠BPD模型修复作用的研究

Bronchopulmonary dysplasia (BPD) is a multifactorial disease, oxidative stress is known to play the key role in the pathogenesis of BPD. Therefore, the pivotal treatment of BPD is to interrupt the oxidative stress cascade and promote lung repair. Previous works from this laboratory demonstrated that rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. But many researches provided the evidence of low engraftment and survival rates of MSCs in models of lung injury, which in part limits application of MSCs in the treatment of BPD. Thioredoxin(Trx) is a kind of oxidant stress-induced protein with antioxidative effect. In preliminary studies, we found that, administration of recombinant human Trx attenuates lung injury induced by hyperoxia through elevation of antioxidant activities and regulation of both MAPK and PI3K-Akt signaling pathways. Otherwise, there is a growing body of evidence suggesting that Trx is involved in survival, proliferation and recruitment of stem cells. However, the recombinant Trx is easy to lose its activity during processing and storage. Based on these pervious data, we suggest that MSCs transfected with Trx have better repairing effect on BPD than single. We would use the rat models developing BPD induced by hyperoxia and the primary cultured type II epithelial cells(AECII) in vitro, which were administrated with MSCs and MSCs transfected with Trx respectively, to prove oxidative stress is the main cause of low engraftment and survival rates of MSCs in models of lung injury, study protective effects of Trx on MSCs, determine whether Trx promote the recruitment of exogenous MSCs homing to and/or participating in rebuilding of missing or damaged lung tissue, and explore synergetic effects of Trx and MSCs on repair of injured lung tissues. If these studies accomplished, the data will be useful for us to better understand the mechanism of MSCs relieving the lung injury and rebuilding of damaged lung tissue, and help us to develop new potential therapies applying MSCs-based cell therapy in the prevention and cure of BPD.

研究显示氧化应激损伤是支气管肺发育不良（BPD）的重要发病机制，寻找切断氧化应激级联反应、促进肺组织修复的有效途径是BPD防治的关键。申请者前期研究发现：间充质干细胞（MSCs）对BPD模型具有修复功能。但由于MSCs肺内植入率低、存活时间短等问题，限制了其应用前景。硫氧还蛋白（Trx）是一种氧化应激诱导蛋白，申请者前期研究显示：在BPD模型中，Trx能通过提高机体抗氧化能力、调控生存信号通路减轻肺损伤。同时，Trx在干细胞的存活、增殖及招募中也有重要的作用。基于上述研究结果，本课题拟建立BPD体内外模型，探讨导致MSCs肺内植入率低的可能机制；并以MSCs为载体进行Trx转染，观察Trx高表达对MSCs生物学特性和肺内植入的影响，以及两者对BPD模型的协同修复作用及其分子机制。本课题将加深对MSCs肺损伤修复作用及机制的了解，为以MSCs为基础的细胞治疗早日应用于BPD治疗提供新思路。

研究显示氧化应激损伤是支气管肺发育不良（BPD）的重要发病机制，寻找切断氧化应激级联反应、促进肺组织修复的有效途径是BPD防治的关键。间充质干细胞（MSCs）对BPD模型具有修复功能。但由于MSCs肺内植入率低、存活时间短等问题，限制了其应用前景。硫氧还蛋白（Trx）是一种氧化应激诱导蛋白，申请者前期研究显示：在BPD模型中，Trx能通过提高机体抗氧化能力、调控生存信号通路减轻肺损伤。同时，Trx在干细胞的存活、增殖及招募中也有重要的作用。本课题研究结果显示，高氧暴露诱导的氧化应激微环境是导致BMSCs死亡的主要机制之一。Trx-1基因修饰BMSCs大大提高了其抗氧化能力，降低了高氧对BMSCs的损伤。以MSCs为载体进行Trx-1转染，与肺泡II型上皮细胞（AECII）共培养，显著减轻了高氧诱导的ECII损伤和凋亡。Trx-1修饰BMSCs后，二者表现出协同修复AECII和新生鼠高氧损伤的能力。本课题目前和进一步的研究成果，将加深对MSCs肺损伤修复作用及机制的了解，为以MSCs为基础的细胞治疗早日应用于BPD治疗提供新思路。