骨髓间充质干细胞微泡水平传递miR-29修复放射性肺损伤的作用及机制研究

Radiation induced lung injury is one of the most common complications during radiotherapy of patients with thoracic tumors, which is the main restraining factor to improve the target dose. It is urgent to find an effective method to treat radiation induced lung injury. It has been proved that bone mesenchymal stem cells (BMSCs) play an important role in lung injury, but the exact mechanism on cross talk between BMSCs and lung epithelial cells is unclear. Microvesicles (MV) secreted by BMSCs are key mediators to transfer the bioinformation between cells. Our previous study has been shown that the miR-29 expression was upregulated in BMSC-MV, and multiple pro-fibrotic genes have been predicted as the potential targets of miR-29 by several bioinformatic softwares. In this research, the experiments on cells and animal models were used to confirm the role of BMSC-MV to repair the radiation-induced lung injury, then the non-contact co-culture system was used to clarify the molecular mechanism of repairment, which was associated with the trefer of miR-29. Additionally, the direct correlations between miR-29 and pro-fibrotic genes were comfirmed by luciferase system. The aim of the study is to clarify the molecular mechanism on BMSC-MV repairment of radiation-induced lung injury, which could offer a new, more effective target for the anti-fibrotic therapy.

放射性肺损伤是胸部肿瘤放疗过程中最常见的合并症，发病率高，成为制约肿瘤靶区剂量提高的主要因素。探寻一种能有效治疗放射性肺损伤措施，具有重要的临床意义。骨髓间充质干细胞(BMSCs)能修复放射性肺损伤，但BMSCs与损伤肺上皮间“cross-talk”的确切机制尚不清楚。BMSCs分泌的微泡(MV)是细胞间信息物质传递的重要介质，前期研究发现，BMSC-MV中miR-29高表达，生物信息学预测发现其下游靶标分子中有多个促纤维化基因。本研究拟首先在细胞和动物模型中证实BMSC-MV对放射性肺损伤的修复作用，采用非接触共培养系统明确MV对肺损伤的修复作用是由水平传递的miR-29介导的，并进一步通过荧光素酶实验证实miR-29与促纤维化分子的直接相互作用，以期阐明BMSCs-MV修复放射性肺损伤分子机制，为抗纤维化治疗提供一个新的更为有效的靶点。

放射治疗是一种重要的局部治疗手段，约2/3的肿瘤患者在治疗的不同阶段都需接受放射治疗。放射性肺损伤(radiation-induced lung injury, RILI)是胸部肿瘤放疗过程中最常见的合并症，发病率高，是制约靶区剂量提高的重要因素，使肿瘤的局部控制受到严重威胁。目前糖皮质激素和抗生素的临床应用虽能在一定程度改善患者症状，但其对损伤细胞尚无确切的修复作用。骨髓间充质干细胞(BMSCs)能修复放射性肺损伤，但其与损伤肺上皮间“cross-talk”的确切机制尚不清楚。因此，积极探寻放射性肺损伤有效、低毒的治疗措施并深入揭示其相关的分子机制具有极其重要的学术和社会经济价值。本研究拟首先在细胞和动物模型中证实BMSC-MV对放射性肺损伤的修复作用，采用非接触共培养系统明确MV对肺损伤的修复作用是由水平传递的miR-29介导，并进一步通过荧光素酶实验证实miR-29与促纤维化分子的直接相互作用，以期阐明BMSCs-MV介导放射性肺损伤修复的分子机制。研究结果证实BMSCs分泌的MV是促进放射性肺损伤修复的重要介质，其修复作用是通过水平传递的miR-29抑制促纤维化基因FSTL1和SPARC表达实现的。该研究深入揭示了BSMCs修复射线损伤肺组织的分子机制，同时为基于MV的“无细胞”移植策略治疗放射性肺损伤提供了部分新的线索和实验依据。