不同表达状态的EDIL3介导的皮肤间充质干细胞在银屑病血管新生中的作用及机理

The abnormal proliferation and enlargement of dermal papillary blood vascular is one of the main pathological features in psoriasis lesions, which is proved to promote the inflammatory response and closely associated with the process of psoriasis. Epidermal growth factor-like repeats and discoidin I-like domains 3（EDIL3）is identified to be a switch that initiates angiogenesis through indung cell adhesion, migration and inhibiting the apoptosis of vascular endothelial cells (VECs), and play an important role in maintaining the morphology and stability of neovascularization, which is regulated by integrin-FAK signal pathway. In our previous study, we found that the expression of EDIL3 were significantly increased in dermal-derived mesenchymal stem cells (DMSCs) from psoriasis. We assumed that the local angiogenesis of skin is regulated by psoriatic DMSCs through EDIL3-mediated integrin-FAK signaling pathways, which are involved in the pathogenesis of psoriasis. In this study,firstly, we will adopt lentivirus infection to regulate the EDIL3 expression on DMSCs in healthy adults and psoriasis in vitro. Next,we will detect the proliferation,apoptosis, adhesion and migration characteristics of VECs,and investigate the capacity of angiogenesis in vitro and in vivo after co-culture with above pre-treated DMSCs. In the end, we perform fluorescent quantitative PCR chip to explore the.molecular mechanism of EDIL3 mediated endothelial function. In conclusion,this study will provide a theoretical basis for explaining the.microvascular abnormalities of pathogenesis and a new target of antiangiogenic therapy of psoriasis in future.

真皮乳头血管异常增生、扩张是银屑病皮损的主要病理特征，且血管增生促进的炎症反应与该病发生、发展密切相关。EDIL3被称为启动血管生成的开关因子，可以诱导血管内皮细胞（VECs）粘附、迁移，抑制其凋亡，对维持新生血管形态及稳定很重要，且该过程受整合素-FAK信号通路调节。前期研究发现银屑病真皮间充质干细胞（DMSCs）EDIL3表达显著增高。设想银屑病DMSCs通过EDIL3介导的整合素-FAK信号通路调控皮肤局部的血管新生，参与了银屑病的发病。本课题拟采用转染方式体外调控患者及正常人DMSCs的EDIL3表达，将干扰后DMSCs与VECs共培养，检测VECs增殖、凋亡、粘附、迁移等生物学特性和体内、外成血管功能，进一步采用荧光定量PCR芯片发掘EDIL3调控VECs功能的信号通路。本研究将为银屑病皮损微血管生成异常提供理论依据，为该病的抗血管生成治疗提供新靶点。

真皮乳头血管异常增生、扩张是银屑病皮损的主要病理特征，且血管增生促进的炎症反应与该病发生发展密切相关。表皮生长因子样重复折叠 1 结构域蛋白 3（Epidermal growth factor-like repeats and discoidin I-like domains 3，EDIL3）被称为启动血管生成的开关因子，可以诱导血管内皮细胞（Vascular endothelial cells，VECs）粘附、迁移，抑制其凋亡，对维持新生血管形态及稳定很重要，且该过程受整合素-FAK信号通路调节。我们前期研究发现银屑病真皮间充质干细胞（Dermal mesenchymal stem cells，DMSCs）中EDIL3表达显著增高。推测银屑病DMSCs通过EDIL3介导的整合素-FAK信号通路调控皮肤局部的血管新生，参与了银屑病的发病。本课题采用了Si-RNA与慢病毒转染方式体外调控患者及正常人DMSCs的EDIL3表达，将干扰后DMSCs与VECs共培养，然后检测VECs增殖活力、凋亡、粘附、迁移等生物学特性和体内、外成血管功能，进一步对EDIL3调控VECs功能的信号通路进行了深入的研究。结果表明高表达EDIL3的DMSCs明显促进了HUVECs的增殖活力；高表达EDIL3的DMSCs明显促进了HUVECs的迁移/黏附与体外血管形成生物学功能的改变及EDIL3-Integrin信号通路关键蛋白整合素αvβ3、α5β1受体、p-FAK、p-MEK、p-ERK表达上调；在咪喹莫特诱导的银屑病样小鼠模型中，注射EDIL3蛋白后红斑鳞屑明显增多、皮肤厚度增加、真皮微血管密度增大，使体外咪喹莫特诱导的小鼠银屑病样皮损在外观及病理表现中均加重，可以使银屑病加重。本课题为间充质干细胞在银屑病发病机理中血管增生的原因提供了理论依据，为今后银屑病治疗研究提供了潜在的治疗靶点。