GO促进BMSCs外泌体分泌诱导成骨分化作用的机制研究

课题组前期研究发现氧化石墨烯（GO）在体外和体内均能够诱导骨髓间充质干细胞（BMSCs）成骨分化，BMSCs源性外泌体分泌增加，integrinα2β1和miR196a表达升高。基于已有研究线索，我们认为GO诱导BMSCs成骨分化可能是激活integrinα2β1，诱导外泌体分泌增加和miR196a表达上调并通过Integrinα2β1-ISG/Cortactin-Exosomes-miR196a-HoxC8-BMP2信号通路实现。为验证该假说，本项目以miR196a为切入点，联合体内外实验通过改变miR196a表达，结合干扰Integrinα2β1-ISG/Cortactin-Exosomes-miR196a-HoxC8-BMP2信号通路上不同位点研究信号传导机制。该项目的实施将揭示GO诱导BMSCs成骨分化的信号传递机制，促进GO骨组织材料临床转化。

Osteogenic induction based on biological materials is always the struggling work in orthopedic biomaterial research. Graphene oxide (GO) is a potential orthopedic biomaterial due to the osteoinductive character to bone mesenchymal stem cells (BMSCs). However, the mechanism of this process is unknown. Our previous study demonstrated that BMSCs seeded on GO membrane completed osteogenic differentiation under non-osteoinductive culture condition. And, the secretion of exosomes and the expression of integrin α2β1 and miR196a increased, and the disturbance of HoxC8-BMP2 pathway can abolish the osteogenic differentiation of BMSCs. Considering the literature reviews and our unpublished results, it’s hypothesized that GO induced osteogenic differentiation of BMSCs may be triggered by activation of integrin α2β1，thereby increasing the secretion of exosomes and the expression of miR196a，which was achieved by Integrinα2β1-ISG/Cortactin-Exosomes-miR196a- HoxC8-BMP2 pathway. To test the hypothesis, we focus on function of miR196a and explore the mechanism of GO induced BMSCs-osteoblast transition in detail through modulating miR196a expression in vitro and in vivo, combined with medication or genetic manipulation of the signaling cascades in this signal pathway. This study is expected to uncover the mechanism of osteogenic differentiation of BMSCs induced by GO, and to provide new insights into osteoinduction biomaterials and reparation of bone defects. This study also holds special hope for providing potential excellent orthopedic biomaterials in the future.