蛋白酪氨酸磷酸酶SHP1对间充质干细胞免疫调节特性的作用及其机制研究

Mesenchymal stem cells (MSCs) are multiple stem cells existing in various tissues. They possess immunomodulatory ability and participate in various immune reaction, such as tumor, inflammatory diseases and so on. However, the detailed mechanisms controlling the immunomodulatory property of MSCs are still elusive. Src Homology 2 (SH2) domain-containing phosphatase-1 (SHP1) is a member of the protein–tyrosine phosphatase (PTP) family, which regulates processes including cell growth, proliferation and activation, closely related with various pathological and physiological processes. Previous reports found that in macrophages and neuroglia cells SHP1 blocked nitric oxide (NO) production, which is a key effector molecule in mediating MSC immunomodulatory property. Therefore, we hypothesize that SHP1 regulates the immunomodulatory property of MSCs, which plays a key role in tumor progression. We are aimed to explore the regulation and mechanism of MSC immunomodulatory property by SHP1, and explain the relation with tumor progression. This project will expand our awareness of the mechanism regulating MSC immunomodulatory property, provide important scientific basis for explaining the relation of MSCs with tumor, and furnish theoretical guidance for clinical MSC treatment in tumor.

间充质干细胞（MSCs）作为一种多潜能干细胞，存在于多种组织中，具有免疫调节功能，参与肿瘤、炎症性疾病等诸多免疫反应。然而，目前调控MSCs免疫调节特性的机制仍不清楚。Src Homology domain-containing phosphatase-1（SHP1）作为蛋白酪氨酸磷酸酶，参与调控细胞增殖、分化、活化等过程，与体内许多病理生理现象相关。研究发现巨噬细胞和神经胶质细胞中SHP1抑制一氧化氮（NO）的产生。由于NO是介导MSCs免疫调节特性关键的效应分子，因此，我们提出假设SHP1调控MSCs免疫调节特性以及该调控作用参与肿瘤的发生发展。本课题拟阐明SHP1对MSCs免疫调节特性的调控作用及其分子机制，阐述SHP1调控MSCs免疫调节特性与肿瘤发生发展的联系；将拓展对MSCs免疫调节特性调控机制的认识，为阐明MSCs与肿瘤的关系提供科学依据，为MSCs在肿瘤治疗中提供理论指导。

间充质干细胞（Mesenchymal Stem Cells, MSCs）作为一种异质的多潜能组织干细胞，广泛存在于机体各种组织中，具有免疫调节功能，参与肿瘤、炎症性疾病等诸多免疫反应。然而，目前调控MSCs免疫调节特性的机制仍不清楚。我们进行了以下研究内容：1）阐明蛋白酪氨酸酶SHP1对MSCs免疫调节特性的调控作用；2）阐述SHP1调控MSCs免疫调节特性的信号通路和分子机制；3）探讨SHP1对MSCs免疫调节特性的调控在肝损伤中的作用。在与脾细胞的共培养体系中，在比例较低，只有mev/mev MSCs表现出较好的抑制效果。使用细胞因子联合刺激MSCs，发现mev/mev MSCs的NO含量、iNOS和Cox2的mRNA水平和蛋白水平均显著上调。在WT MSCs上过表达SHP1后，NO含量、iNOS和Cox2的mRNA水平均显著下调。研究表明SHP1负性调节多种信号通路，其中包括JAK/STAT信号。因此，我们分别用因子联合处理mev/mev和WT-MSCs，发现JAK1、STAT3和p38的磷酸化显著增加。为探讨SHP1在体内对MSCs免疫抑制的调节作用，我们采用ConA诱导的肝损伤模型，同时经尾静脉移植MSCs。有趣的是mev/mev-MSCs则几乎消除了肝脏损伤，并显著降低了血清ALT和AST水平。结果表明，SHP1在体内对MSCs的免疫抑制具有重要的调节作用。本课题拓展了对MSCs免疫调节特性分子机制的认识，为阐明MSCs免疫调节特性与肝损伤的关系提供关键的科学依据。