CD26调控骨髓来源细胞对脉络膜新生血管的作用及其机制研究

The bone marrow-derived cells (BMCs) participate in choroidal neovascularization. In recent studies, much attention was paid to the repairing and regenerating functions of transplanting BMCs by intraocular injection in the pathological process of CNV. However, there are very limited BMCs in the peripheral circulation. Technology has not yet reached a stage where ex vivo-expanded BMCs can be routinely used for cell therapy. A recent finding has shown that SDF-1 degradation and inactivation within the bone marrow by CD26 may ultimately result in the mobilization and expansion of BMC. We has experimented and reported that a subgroup of cells in BMCs-endothelial precursor cells (EPCs)-could be mobilized and expanded by mediating CD26. In our results, we observed that the severity of CNV was decreased. Therefore, we hypothesized that enough autologous cells provided by expanding BMCs in vivo would play a repairing role in CNV. In this study, we plan to establish a C57BL/6J-GFP hybrid model of mouse by the laser-induced method. The roles and mechanisms of CD26 mediating BMCs in choroidal neovascularization will be studied through a diversity of ways, including FACS, WB, RT-RCR, ELISA etc. We believe the results of this study will equip us a new strategy of BMCs treating CNV finally.

骨髓来源细胞(BMCs)参与脉络膜新生血管(CNV)的形成。近年来的研究多关注眼内移植BMCs在CNV的再生和修复作用。但BMCs在外周循环的数量有限，目前的技术和条件尚不能使体外扩增的BMCs被常规用于细胞治疗。已经证实调控CD26蛋白水解活动可降解和失活骨髓内的SDF-1，动员扩增体内的BMCs。我们近期的研究工作报道了CD26调控BMCs的一个亚群——内皮祖细胞(EPCs)的体内动员扩增，能够减轻CNV。因此我们推测，通过体内扩增BMCs能够提供充足的自体细胞，在CNV中发挥内源性的损伤修复作用。本课题拟在前期研究基础上，建立激光诱导的C57BL/6J-GFP嵌合体小鼠CNV 模型，利用FACS,WB, RT-RCR, ELISA及免疫荧光标记等方法，研究CD26调控BMCs在CNV血管损伤区可能的分化潜能及细胞治疗潜力，阐明具体的作用机制，为BMC细胞治疗CNV提供新的治疗策略。

骨髓来源细胞(BMCs)参与脉络膜新生血管(CNV)的形成。眼内移植BMCs在CNV的再生和修复作用是近年来最被关注的热点问题。但BMCs在外周循环的数量有限，目前的技术和条件尚不能使体外扩增的BMCs被常规用于细胞治疗。我们的前期研究已经证实CD26/DPP IV蛋白水解活动可降解和失活骨髓内的基质细胞衍生因子（SDF-1），动员扩增体内BMCs的一个亚群——内皮祖细胞（EPCs）减轻CNV。因此本课题在前期研究基础上，建立稳定的激光诱导C57BL/6J-绿色荧光蛋白（GFP）嵌合体小鼠CNV模型，利用体内体外实验方法，深入研究CD26调控BMCs动员扩增自体细胞在CNV血管损伤区可能的分化潜能及细胞治疗潜力。研究结果初步证实激活体内CD26肽酶系统可有效的动员扩增体内BMCs，增加BMCs募集迁移到CNV，发挥治疗作用。BMC细胞治疗CNV的机制可能涉及体内动员扩增的BMCs归巢分化成视网膜色素上皮细胞（RPEs）发挥再生修复作用；激活小神经胶质细胞的应答，活化神经胶质分泌神经营养因子有保护作用；募集骨髓来源的巨噬细胞到CNV损伤区，分泌抗炎介质发挥抗炎作用。体内动员BMCs通过内源性的损伤修复途径抑制了激光诱导的CNV。这样的治疗策略可能使以往仅限于局部治疗CNV，转变到通过全身干预的治疗模式，从局部侵入性的给药方式转变到全身治疗更安全的模式。本课题研究结果初步探索了BMCs在CNV的发生、发展和治疗中的作用。为BMC细胞治疗眼微血管疾病转入临床应用提供新的思路。