骨髓交感神经Schwann细胞损伤介导nestin+MSCs 凋亡在ITP血小板生成减少中的作用机制

Thrombocytopenia is one of the pathogenesis, Hoverer, immature of megakaryocytes is critical role in immune thrombocytopenia (ITP) ,Thus it is of great importance to further investigate into the pathogenesis of ITP. Our previous studies first demonstrate bone marrow sympathetic nerve fiber damage in ITP patients and elucidated abnormal apoptosis and senescence as well as reduced expression of nestin of mesenchymal stem cells (MSCs) in ITP patients. This project is designed to further investigate bone marrow sympathetic nerve fiber damage with increased apoptosis of supporting Schwann cells, and its regulation of megakaryocytes signaling through CXCL12/CXCR4 in bone marrow microenvironment, aiming to explore the patterns of megakaryocyte migration in vascular niche and the role of TNFAIP3/SMAD7 signaling pathway. It strongly suggests a novel theory of ITP that sympathetic nerve damage reduces nestin+ MSCs, impairing megakaryocyte differentiation and maturation. Bone marrow sympathetic nerve damage in ITP patients might be a promising therapeutic target.

血小板生成减少是免疫性血小板减少症（ITP）重要发病机制，而巨核细胞成熟障碍是血小板生成减少发病的核心环节，进一步阐明血小板生成减少及其机制，有重要的临床和理论意义；申请者在前期研究中，首次意外发现ITP患者骨髓交感神经病变，以及Schwann 细胞的损伤，并导致nestin+ 间充质干细胞（MSCs）异常凋亡；强烈提示ITP患者骨髓交感神经损伤介导nestin+ MSCs凋亡是巨核细胞成熟障碍新的发病机制，这一新发现国内外未见报道。本课题拟通过体内外研究，探讨ITP骨髓交感神经纤维病变和Schwann 细胞凋亡的病因，深入研究CXCL12/CXCR4对骨髓微环境巨核细胞成熟的调控；初步阐明TNFAIP3/SMAD7信号通路介导ITP巨核细胞在骨髓微环境迁移、分布和成熟机制以及关键性调控；ITP骨髓交感神经损伤的修复，有望成为临床潜在治疗靶点，为ITP防治策略提供新的理论依据。

本课题通过体内外研究，探讨ITP骨髓交感神经纤维病变和Schwann 细胞凋亡的病因，免疫血小板减少症中与nestin(+)间充质干细胞相关的巨核细胞分布失调,深入研究CXCL12/CXCR4对骨髓微环境巨核细胞成熟的调控；初步阐明了TNFAIP3/SMAD7信号通路介导ITP巨核细胞在骨髓微环境迁移、分布和成熟机制以及关键性调控。我们还发现免疫血小板减少症患者骨髓间充质干细胞通过Notch-1/Jagged-1信号通路诱导树突状细胞分化的功能受损，MSCs缺乏通过A20/NF-κB/SMAD途径影响免疫血小板减少症患者的巨核细胞生成，β2-GPI的表达减少与减轻抗GPIIb / IIIa介导的免疫血小板减少症中补体激活的能力降低有关。全反式维甲酸通过调节补体-IL-1β环路保护间充质干细胞免受免疫性血小板减少影响。靶向IGF2BP1的MiRNA-98-5p通过调节免疫血小板减少中的PI3K/Akt和p53诱导间充质干细胞凋亡。