NRP2不同表达状态对银屑病骨髓和皮肤间充质干细胞分化为血管内皮细胞的影响

Hyperplasia and hyperpermeability of microvessel, increased adhesion and infiltration of inflammatory cells are main pathological characteristics of psoriatic lesion. We have previously found that bone marrow mesenchymal stem cells (BMSCs) derived from patients with psoriasis trend to differentiate into vascular endothelial cell (VEC), and those angiogenesis related genes such as vascular endothelial growth factor (VEGF) coreceptor Neuropilin 2（NRP2）、transcription factor GATA-6 are differently expressed in dermal MSCs（DMSCs）.MSCs are pluripotent stem cells and can be induced to differentiate into VEC under specific conditions. VEGF signaling pathway plays an important regulatory role in the differentiation of MSCs to VEC. So we speculate that the VEGF signaling pathway mediated by NRP2 may play a key role in the spontaneous VEC differentiation tendency of psoriatic MSCs.Therefore, the current study plan to interfere with the expression of NRP2 at BMSCs and DMSCs from patients and normal controls and then induced them to differentiate into VEC; detect the dynamic varitaion of VEGF signaling pathway during the differentiation process; and compare the function of induced VEC with those VEC separated form psoriatic lesions. The in vitro experiment will be confirmed by in vivo study using a NRP2-/- transgenic mice. The results of this study will provide a powerful explanation for why the BMSCs of patients with psoriasis tend to differentiate into VEC, and will lead a new direction of the vascular research of psoriasis.

真皮微血管增生扩张、通透性增高、对炎症细胞的粘附、渗透作用增强是银屑病皮损局部重要的发病特点。我们前期发现本病患者骨髓间充质干细胞（BMSCs）易于向血管内皮细胞（VEC）分化，进一步发现真皮MSCs（DMSCs）中与血管生成相关的基因表达异常，主要表现为VEGF协同受体如NRP2高表达、抑制血管生成基因如GATA-6低表达。MSCs在特定条件可分化为VEC，这一过程受VEGF信号通路调节。故我们推测，NRP2介导的VEGF信号可能在银屑病MSCs向VEC分化异常中起关键作用。因此，本研究拟体外干扰患者及对照骨髓和真皮MSCs的NRP2表达，将干扰后MSCs定向诱导为VEC，检测分化过程中VEGF信号通路的动态变化及分化后VEC的功能，且与患者皮损VEC比较，并构建NRP2-/-小鼠模型验证体外结果。课题将为解释银屑病MSCs为何易于向VEC分化提供理论依据，为银屑病血管研究提供新的方向。

真皮微血管增生扩张、通透性增高、对炎症细胞的粘附、渗透作用增强是银屑病皮损局部重要的发病特点。我们前期发现银屑病患者骨髓间充质干细胞易于向血管内皮细 胞分化，进一步发现皮肤间充质干细胞中与血管生成相关的基因表达异常，故本项目对银屑病皮肤间充质干细胞体外分化血管内皮细胞活性及RNA表达谱等进行了深入研究 。银屑病皮肤间充质干细胞体外分化血管内皮细胞研究结果显示银屑病患者来源的皮肤间充质干细胞体外分化为血管内皮细胞时间缩短，且与PASI评分呈正相关，有家族史患者较无家族史患者分化所需时间缩短；银屑病皮肤间充质干细胞RNA表达谱结果显示，银屑病皮肤间充质干细胞在环状RNA-microRNA-mRNA调控轴上存在异常，特别是在靶基因为炎症与血管形成相关基因的调控方面；银屑病皮肤间充质干细胞与HacaT细胞共培养后，结果显示银屑病皮肤间充质干细胞促进HacaT增殖能力增高，且抑制HacaT细胞的凋亡。课题为间充质干细胞在银屑病中的重要角色提供了理论依据，为银屑病治疗研究提供了新的方向。