骨骼干细胞在放射性骨损伤修复中的作用及对Wnt/β-catenin通路的影响

Radiation-induced bone injury has a baneful influence on human health and life quality of cancer patients, which is a hot topic in the field of radiation medicine. However, the treatment methods for improving bone functions are limited. Skeletal stem cells are abundant and have wide application prospects in molecular diagnosis and treatment of various skeletal diseases. We innovatively propose to use skeletal stem cells in the repair of bone injury induced by irradiation. The animal model of bone injury induced by irradiation will be established, based on which the effects of acute high dose radiation on bone, osteoblasts, osteoclasts and skeletal stem cells will be observed and the dose-response relationship will be built. Allogeneic transplantation of skeletal stem cells will be used to treat radiation-induced bone injury, and the therapeutic effects will be evaluated. The outcome measures include: bone histology, pathological morphology, biochemical indicators and gene expressions in Wnt/beta-catenin pathway. Wnt knockdown mouse model using conditional RNA interference will be used to study the mechanisms of Wnt/beta-catenin pathway in the repair of radiation-induced bone injury. The results of this study will provide theoretical basis and new strategies for clinical treatment of radiation-induced bone injury.

放射性骨损伤对人体健康和患者生活质量影响大，是放射医学研究领域的热点，但改善骨骼功能的治疗方案仍十分有限。骨骼干细胞来源丰富且在多种骨骼疾病分子诊断和治疗方面具有广阔的应用前景。本项目创新性地将骨骼干细胞运用在放射性骨损伤修复治疗中，通过建立放射性骨损伤动物模型，观察并分析急性大剂量辐射对骨、成骨细胞、破骨细胞及骨骼干细胞损伤的剂量效应关系，采用异体动物移植骨骼干细胞治疗放射性骨损伤并评估疗效，疗效指标包括骨组织学、病理学形态、生化指标及Wnt/β-catenin通路中基因表达情况，进一步采用WntRNAi转基因小鼠研究Wnt/β-catenin通路在放射性骨损伤修复中的作用机制。本研究成果将为放射性骨损伤临床治疗提供理论依据和新策略。

放射性骨损伤对人体健康和患者生活质量影响较大，是放射医学领域的研究热点，但改善骨骼功能的治疗方案仍十分有限。骨骼干细胞在多种骨骼疾病诊断和治疗方面具有广阔的应用前景。本项目建立了急性放射骨损伤小鼠模型，采用磁珠分选和流式分选相结合的方法构建了骨骼干细胞体外分离培养技术。进一步研究发现8 Gy X射线照射可造成成骨细胞损伤和凋亡，同时辐射抑制成骨前体细胞的分化、增殖、迁移。采用成骨前体细胞与骨骼干细胞共培养48 h，发现骨骼干细胞可改善成骨前体细胞的矿化和迁移能力，并抑制凋亡。通过转录组测序及KEGG通路富集分析发行骨骼干细胞对受辐照成骨前体细胞的修复作用与Wnt/β-catenin通路有关。进一步实验研究发现骨骼干细胞通过Wnt/β-catenin通路调节成骨细胞分化、恢复成骨细胞功能。小鼠体内实验结果提示局部注射骨骼干细胞可改善小鼠放射性骨损伤。本研究成果将为放射性骨损伤临床治疗提供理论依据和新策略。