脂肪间充质干细胞重塑视网膜新生血管中迁移、分化及信号传导的机制研究

Retinal disease caused by retinal cell apoptosis leads to irreversible vision loss. Stem cell investigation efforts have been made to solve and cure retinal disorders. There are several sources of stem cells which have been used in these experiments. Among these, mesenchymal stem cells (MSCs) were considered a promising source for cell therapy. In this study, vitro experiments were conducted to study the effects of mouse adipose-derived mesenchymal stem cells induced vascular endothelial cells and neuronal cell, also cytological and functional of cells change in hypoxic conditions. In addition, vivo experiments were conducted to study the cells migration and differentiation about retinal neovascularization, especially regulation mechanism of signal transduction.In order to provide theoretical and experimental basis.

视网膜疾病所引起的视网膜细胞凋亡常常导致不可逆转的视力丧失。近年来，通过对干细胞研究，已经可以用于治疗视网膜疾病。在这当中，间充质干细胞被认为是前景光明的治疗细胞。本研究拟通过体外实验研究鼠脂肪间充质干细胞向血管内皮细胞、神经细胞诱导转化以及在低氧状况下的细胞学及功能学改变；此外，通过体内实验研究鼠脂肪间充质干重塑治疗鼠视网膜新生血管的有效性、体内迁移、分化，特别是体内信号传导调控的机制，为脂肪间充质干细胞靶向性治疗视网膜血管性疾病的提供理论及实验依据。

糖尿病视网膜病变等眼部新生血管性疾病会导致不可逆的视力丧失，并且这些疾病的发病率逐年增加。干细胞治疗为此类疾病带来新的希望，但“干细胞疗法”尚未获得美国FDA批准，临床应用有效性及安全性存在争议。本研究使用鼠脂肪间充质干细胞，研究其体外诱导为内皮样细胞及视网膜色素上皮样细胞的可能性，并进一步研究其体内抑制视网膜新生血管的有效性，机制，分化转归及眼内应用安全性。本研究显示，鼠脂肪间充质干细胞诱导后可表达内皮细胞及神经样细胞标记物Pan-CK及vWF，抑制早产儿视网膜病变动物模型新生血管面积（减少95.7%）及无灌注区面积（减少87.3%），体内应用后可以主动移动到病变区域，并不与宿主融合，没有增殖及副反应出现。其作用机制可能为通过旁分泌下调VEGF、HIF-1a、FGF2 表达量来抑制新生血管，上调BDNF、CNTF、EPO 表达量来抗氧化损伤。可能激活的作用通路与炎症和新生血管密切相关，包括白细胞外渗、骨关节炎信号传导和 STAT3 通路。本研究为间充质干细胞及其眼内应用提供了理论依据。