CXCL12/PF4双重调控HSCs功能在免疫性血小板减少症中的作用机制

Defect in thrombopoiesis has recently been a core in the pathogenesis of immune thrombocytopenia (ITP). To elucidate the role of hematopoietic stem cells (HSCs) of the bone marrow niche in the ITP pathogenesis may be a major strategy to overcome the barrier of ITP treatment. The development of ITP may be associated with the modulation of HSCs quiescence and proliferation by multiple cell types. Little is known about the molecular control of HSCs in the bone marrow niche because the research about HSCs in the bone marrow niche is still starting up till now. Our previous findings demonstrate abnormal expression of CXCL12 and PF4 in the bone marrow niche of ITP patients, which is related with dysfunction of HSCs and pathogenisis of ITP. This project will aim at the CXCL12/PF4 modulation of HSCs function via mesenchymal stem cells (MSCs) and megakaryocytes, and reveal the unbalance of HSC quiescence-activation in ITP and its influence on the adhesion, migration and proplatelet formation (PPF) of megakaryocytes in the bone marrow niche. The core issue of our project is to seek out the key cellular and/or molecular targets, explore the mechanisms in depth, expand the theories of ITP pathogenesis and finally, provide new targets and strategy for ITP prophylaxis and treatment.

血小板生成障碍是免疫性血小板减少症（ITP）的核心发病机制。阐明微环境造血干细胞（HSCs）在其发病机制中的作用，可能是突破ITP治疗瓶颈的主要策略之一。骨髓微环境多种细胞及细胞因子对HSCs功能的影响，可能与ITP的发生发展密切关联。国内外对骨髓微环境HSCs在ITP发病中作用的研究尚处于起步阶段，对其分子调控机制更是知之甚少。本课题前期研究发现ITP骨髓微环境CXCL12/PF4表达异常，与HSCs功能改变是ITP特征性改变。本课题拟在体内外研究CXCL12/PF4对HSCs静息-增殖-分化的双重调控，初步阐明HSCs静息-增殖失衡，对巨核细胞（MKs）的黏附、迁移和前血小板生成的影响，揭示ITP血小板生成减少骨髓微环境中MKs和MSCs对HSCs的调控机制，拓展ITP的发病机制理论，为ITP的防治提供新靶点和新策略。

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。我们也发现miR-98-5p靶向IGF2BP1在ITP-MSCs中发挥促凋亡作用，由此产生的IGF-2/PI3K通路抑制和p53积累参与了ITP-MSC凋亡。ATRA可通过抑制miR-98-5p的表达来保护ITP- MSCS免于凋亡，这为ITP提供了一种潜在的治疗方法。我们还发现，增强的复合物活化和相关的促炎细胞因子IL-1β可诱导ITP中骨髓MSC功能障碍，从而引起小位CXCL12的动态变化和骨髓中巨核细胞位置的改变。ATRA是修复原发性ITP患者MSC功能障碍的一种有前途的治疗方法。通过临床研究发现，全反式维甲酸和大剂量地塞米松联合治疗新诊断的免疫性血小板减少症患者是一种安全有效的一线治疗方法。与单独使用高剂量地塞米松相比，全反式维甲酸和高剂量地塞米松在6个月时的副作用很少且轻微，可提高持续缓解率，降低临床显著出血的风险，改善健康相关的生活质量。