肝细胞生长因子调节人骨髓基质干细胞成骨分化的效应与机制

Avascular necrosis (ANFH) is frequently occurring in clinic with high morbidity. Although there is no effective therapy for ANFH at present, bone marrow stromal stem cell (BMSC) transplantation holds great promise. Previously supported by State 863 Projects, we made the first attempt to develop the therapeutic technology platform for early ANFH based on transplantation of hepatocyte growth factor (HGF) gene-modified BMSC in combination with core decompression. The feasibility and effectiveness of this original strategy obtained verification in the animal model. Further exploration of the mechanisms led to the finding that the HGF level is involved in the regulation of proliferation and osteogenic differentiation of BMSC. Based on our previous studies, we intend to find out the optimal levels of HGF gene modification for regulating proliferation and osteogenic differentiation of human BMSC. Further, we will explore the regulatory mechanisms by the HGF/c-Met signaling pathway in this process, and access to the best regimen of the specific signal pathway inhibitor / activator usage for assisting the osteo-inductive effects of HGF. Such assistant regimen is to be validated in the rabbit model of early hormonal ANFH. This project will provide more solid basis for the clinical application of HGF gene-modified BMSC transplantation for treatment of early ANFH.

股骨头缺血性坏死（ANFH）是临床多发病和常见病，致残率极高，目前尚无特效疗法。骨髓基质干细胞（BMSC）移植疗法治疗ANFH前景广阔。项目组前期在863计划的资助下，建立了肝细胞生长因子（HGF）基因修饰BMSC移植联合髓芯减压治疗早期ANFH的技术平台，其可行性和有效性在动物模型中获得验证；进一步探讨疗效产生的机制，发现HGF水平可调控BMSC的增殖与成骨分化。本项目拟在人BMSC中找到调控BMSC增殖与成骨分化的最适HGF基因修饰水平，并进一步探讨HGF及其受体c-Met下游信号通路在此过程中的调控机制，同时获得可辅助HGF诱导成骨的最佳信号通路特异性抑制剂/激活剂使用方案，进而在兔早期激素性ANFH模型中进行验证。本项目将为HGF基因修饰BMSC移植治疗早期ANFH的临床应用提供更坚实的依据。

股骨头缺血性坏死（ANFH）是临床多发病和常见病，发病率呈逐年上升趋势。尽管治疗该病的方法从保守到手术层出不穷，但仍然没有一种特效方法，高致残率造成新的社会负担。加快研发新技术，为ANFH提供有效的治疗手段，其社会迫切性以及潜在的商业价值是不言而喻的。组织工程与干细胞技术的迅速发展，为骨组织缺损的修复和功能性的重建提供了理想的方法。本研究前期所建立的HGF基因修饰BMSC移植联合髓芯减压治疗早期ANFH的技术，提高了生物治疗的效率，为ANFH治疗提供了一种全新的模式。. 为推动HGF基因修饰BMSC移植疗法治疗ANFH的临床应用，本研究在人BMSCs中，检测了不同MOI的rAd-HGF诱导人BMSC增殖与成骨分化的效应，并探讨了其中的c-MET及其下游信号通路机制。研究证实，①以较高MOI感染实现的HGF基因修饰可在生长环境中显著促进人BMSCs的增殖，但在成骨诱导环境中会抑制细胞增殖。②相反，在成骨诱导环境中，以较高MOI的rAd-HGF感染可显著促进人BMSCs的成骨分化。③在此过程中，c-MET活化介导了较高水平HGF的促成骨效应，但抑制了较低水平HGF的促成骨效应。④WNT通路不参与HGF诱导的BMSCs增殖效应调控，但在HGF诱导的成骨分化效应中具有显著的抑制效应。⑤ERK1/2通路介导了HGF促进人BMSCs增殖的效应，但不参与HGF对成骨分化的调控。⑥PI3K/AKT通路不参与HGF诱导的增殖效应，但在HGF诱导的人BMSCs成骨分化中发挥重要的促进效应。

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