椎间盘退变(IVDD)及其继发疾病是重要临床问题,髓核细胞(NPC)数量减少和功能下降是其直接诱因,骨髓间充质干细胞(BMSC)因能分化为NPC是IVDD生物治疗的理想种子细胞。但目前BMSC向NPC分化效率较低且机制不清，故深入研究其分化机制对于提高分化效率十分关键。申请人曾报道Notch 信号能调控NPC增殖及合成细胞外基质,然其在BMSC分化中作用不清？预实验发现BMSC向NPC分化时Notch2/JAG1表达显著升高;抑制Notch信号增加BMSC凋亡,抑制其向NPC分化,并抑制分化后NPC合成细胞外基质,提示Notch2/JAG1在BMSC向NPC分化过程中至关重要。故我们假设:Notch2/JAG1能抑制BMSC凋亡,促进其向NPC分化并维持分化后NPC合成细胞外基质。进一步将采用慢病毒基因沉默等技术检测上述假设的正确性及具体机理。本研究将为IVDD的细胞生物治疗提供新的方向

Intervertebral disc degeneration and its secondary disease are major clinical problems, causing heavy burden to the society, surgery and medication can’t solve the IVDD problem fundamentally, the loss of nucleus pulposus cells and decreased extracellular matrix synthesis can directly cause IVDD, so cell therapy is the ideal treatment. Previous studies have confirmed that bone marrow mesenchymal stem cells (BMSCs) can differentiate into nucleus pulposus (NP) cells, therefore it is the ideal seed for biological treatment of IVDD with good prospects, but its differentiation rate is low. Currently, culture condition of BMSCs differentiation into NP cells is not good, and the mechanism is unclear. However, the differentiation rate can’t reach optimum level just by improving culture condition, so it is very important to investigate the mechanism of BMSCs differentiation into NP cells. Our prior data showed that Notch2/JAG1 highly expressed during the differentiation of BMSCs into NP cells; And Notch signal inhibitor can induce BMSCs apoptosis, suppress the differentiation of BMSCs into NP cells, and inhibit the secretary of extracellular matrix, which suggested Notch2/JAG1 play an important role in the differentiation of BMSCs into NP cells. According to these, we bring up the hypothesis: Notch2/JAG1 can suppress the apoptosis of BMSCs, promote the differentiation of BMSCs into NP cells and maintain its functions about secrete extracellular matrix. The objectives of this project are: to explore the detail role and mechanism of Notch2/JAG1 inhibiting the apoptosis of BMSCs; to study the role of Notch2/JAG1 in the differentiation of BMSCs into NP cells; to investigate the molecular mechanism of Notch/JAG1 in promoting BMSCs differentiate into NP cells and maintain the function of NP cells. This project is designed to investigate the role of Notch2/JAG1 in the differentiation of BMSCs into NP cells and its mechanism, which can provide a new way for the biological treatment for intervertebral disc degeneration.