Lu Weifeng, Chen Xiaoli, Si Yi, Hong Shichai, Shi Zhengyu, Fu Weiguo
Department of Vascular Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China.
Cancer Research Center, Medical College of Xiamen University, Xiamen, China.
Stem Cells Int. 2017;2017:3794817. doi: 10.1155/2017/3794817. Epub 2017 Nov 7.
Mesenchymal stem cells (MSCs) have been increasingly tested in cell-based therapy to treat numerous diseases. Genetic modification to improve MSC behavior may enhance posttransplantation outcome. This study aims to test the potential therapeutic benefits of rat bone marrow MSCs overexpressing hypoxia-inducible factor 2 (rMSCs ) in a rat hindlimb ischemia model. PBS, rMSCs, or rMSCs were injected into rat ischemic hindlimb. Compared with the injection of PBS or rMSCs, transplantation of rMSCs significantly improved blood perfusion, increased the number of vessel branches in the muscle of the ischemic hindlimb, and improved the foot mobility of the ischemic hindlimb (all < 0.05). rMSC transplantation also markedly increased the expression of proangiogenic factors VEGF, bFGF, and SDF1 and Notch signaling proteins including DII4, NICD, Hey1, and Hes1, whereas it reduced the expression of proapoptotic factor Bax in the muscle of the ischemic hindlimb. Overexpression of HIF-2 did not affect rMSC stemness and proliferation under normoxia but significantly increased rMSC migration and tube formation in matrigel under hypoxia (all < 0.05). RMSCs stimulated endothelial cell invasion under hypoxia significantly ( < 0.05). Genetic modification of rMSCs via overexpression of HIF-2 improves posttransplantation outcomes in a rat hindlimb ischemia model possibly by stimulating proangiogenic growth factors and cytokines.
间充质干细胞（MSCs）已越来越多地在基于细胞的治疗中进行测试，以治疗多种疾病。通过基因改造来改善MSC的行为可能会提高移植后的疗效。本研究旨在测试在大鼠后肢缺血模型中过表达缺氧诱导因子2的大鼠骨髓间充质干细胞（rMSCs）的潜在治疗益处。将磷酸盐缓冲液（PBS）、rMSCs或rMSCs注射到大鼠缺血后肢。与注射PBS或rMSCs相比，rMSCs移植显著改善了血液灌注，增加了缺血后肢肌肉中的血管分支数量，并改善了缺血后肢的足部活动能力（均P<0.05）。rMSCs移植还显著增加了促血管生成因子血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）和基质细胞衍生因子1（SDF1）以及Notch信号蛋白（包括DII4、NICD、Hey1和Hes1）的表达，而降低了缺血后肢肌肉中促凋亡因子Bax的表达。在常氧条件下，缺氧诱导因子2（HIF-2）的过表达不影响rMSCs的干性和增殖，但在缺氧条件下显著增加了rMSCs在基质胶中的迁移和管形成能力（均P<0.05）。rMSCs在缺氧条件下显著刺激内皮细胞侵袭（P<0.05）。通过过表达HIF-2对rMSCs进行基因改造可能通过刺激促血管生成生长因子和细胞因子来改善大鼠后肢缺血模型中的移植后疗效。
