干扰素γ通过调控间充质干细胞的自我更新能力影响骨重塑

The skeleton of human and animals maintain metabolic balance in the process of bone remodeling that involves break down and build up of bone. Mesenchymal stem cell (MSC) has been an important participant for bone remodeling because of its self-renew property, multilineage differentiation ability for bone generation and its osteoclastogenesis modulating capacity for bone resorption. Interferon-gamma (IFN-γ), mainly secereted by immune cells, is a pivatol cytokine for immune modulation. In spite of its well underding in the immune disorders, the modulatory effect of IFN-γ on bone remodeling remains controversial. Our recent works accidentally discovered that IFN-γ modulates the self-renewal of MSC to maintain the number of osteoprogenitors. In addition, the IFN-γ deficient mouse exhibits osteodysplasty. The colony forming capacity of compact bone derived MSC from the mouse was impaired and the effect was closedly bound up with the expression of some transcription factors including Nanog，OCT-4 and SOX-2. Hence, this proposed study will mechanistically investigate the regulation of IFN-γ on bone remodeling by the self-renewal of MSC through studying the model of LPS mouse and CIA mouse. This study will shed light on the comprehensive understanding of modulatory effct of IFN-γ on MSC; thus contribute to theoretical accumulation in the field of bone remodeling and provide new theoretical guidance for the clinical application of MSC.

人和动物的骨骼通过骨重塑作用保持代谢平衡。间充质干细胞（MSC）是骨重塑的重要参与者，它既能自我更新，多向分化，促进骨的再生，又能调节破骨细胞的发育和功能，影响骨再吸收。γ干扰素（IFN-γ）主要由免疫细胞分泌，以往研究多侧重其免疫调节功能，有关其对骨重塑的作用报道不多。我们近期的工作意外发现IFN-γ能够调节MSC的自我更新能力，维持成骨前体细胞数量稳定。IFN-γ敲除后，小鼠骨发育迟缓，密质骨中的MSC集落形成能力受损，且与转录因子Nanog，OCT-4和SOX-2表达密切相关。而目前国内外研究未见IFN-γ调节MSC自我更新能力及其机制的报道。为此，本课题拟用基因敲除鼠建立CIA小鼠和LPS小鼠骨损伤模型，研究IFN-γ对MSC自我更新能力的调节及对骨重塑的影响和机制。本课题有助于全面了解IFN-γ对MSC的调控作用，将为骨重塑研究领域提供理论积累，为MSC临床应用提供新的理论依据。

γ干扰素（IFN-γ）是一种主要由免疫细胞分泌的免疫调节因子，以往的研究主要关注其在感染免疫、移植免疫和肿瘤免疫中的作用，有关其在骨等重要组织再生修复中的作用认识的不多。干细胞是组织再生的重要种子细胞，深入探索IFN-γ对MSC的影响有助于优化骨再生的效率。本课题首先分析了IFN-γ缺失后，小鼠骨骼发育的异常情况；其次检测了IFN-γ缺失后骨来源MSC的自我更新能力下降；再次，采用高通量技术分析了IFN-γ作用后MSC内关键基因表达的变化。此外，我们还关注了1）IFN-γ诱导的细胞间粘附分子1（ICAM-1）在体内外对MSC成骨分化的负调控作用，2）MSC对于骨再生关键材料聚乳酸羟基乙酸诱导的树突状细胞以及T细胞的调控作用，发现了MSC可以在该种再生条件下抑制IFN-γ分泌。3）造血干细胞移植后骨髓微环境中的MSC可以抑制T细胞分泌IFN-γ分泌，促进微环境重建等等重要发现。