Shi Shuo, Zhang Min, Guo Rui, Miao Ying, Zhang Xiangming, Li Biao
Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197, Ruijin Er Rd, Shanghai 200025, China.
Curr Gene Ther. 2015;15(5):460-71. doi: 10.2174/1566523215999150421164034.
Heart tissue has a diminished ability to repair after myocardial infarction (MI). Bone marrow- derived mesenchymal stem cells (BMSCs) have been used effectively to heal damaged tissue after MI. Hypoxia-inducible factor-1α (HIF-1α) can induce transcription of numerous pro-angiogenic genes and enhance stem cell survival. Here, we investigated whether HIF-1α-transduced BMSCs could enhance tissue repair after MI, and compared the value of micro-PET/CT and echocardiography for evaluation of therapeutic effects. Rat BMSCs were transduced with a lentivirus expressing HIF-1α and NIS (Lenti-HIF-1α-NIS). Sodium iodide symporter (NIS) functioned as effective reporter gene, allowing monitoring of BMSCs transplanted into the rat heart for up to 2 weeks using micro-SPECT/CT imaging. In a rat MI model, after transplantation of HIF-1α-NIS-transduced BMSCs to the MI zone, more expression of HIF-1α,VEGF and Ang-4, more improvement of metabolism, less fibrotic tissue and cardiomyocyte apoptosis were detected in the MI zone. Moreover, we found that most of the transplanted HIF-1α-NIS-transduced BMSCs differentiated into endothelial cells, and engineered new blood vessels in MI zone. Metabolic activity significantly increased at an early time point (2 weeks after transplantation) and lead to a sustained increase (4 weeks), as indicated by (18)F-FDG uptake in micro-PET/CT imaging. Echocardiography indicated no improvement in cardiac function at 2 weeks and small improvement at 4 weeks. This study indicated that (18)F-FDG micro-PET/CT was more useful for evaluating early therapeutic effects than echocardiography.
心肌梗死后，心脏组织的修复能力会降低。骨髓间充质干细胞（BMSCs）已被有效地用于心肌梗死后受损组织的修复。缺氧诱导因子-1α（HIF-1α）可诱导众多促血管生成基因的转录，并提高干细胞的存活率。在此，我们研究了转导HIF-1α的BMSCs是否能增强心肌梗死后的组织修复，并比较了微型PET/CT和超声心动图在评估治疗效果方面的价值。用表达HIF-1α和钠碘同向转运体（NIS）的慢病毒转导大鼠BMSCs（慢病毒-HIF-1α-NIS）。钠碘同向转运体（NIS）作为有效的报告基因，可使用微型SPECT/CT成像监测移植到大鼠心脏中的BMSCs长达2周。在大鼠心肌梗死模型中，将转导HIF-1α-NIS的BMSCs移植到梗死区域后，在梗死区域检测到更多的HIF-1α、血管内皮生长因子（VEGF）和血管生成素-4（Ang-4）表达，代谢改善更多，纤维化组织和心肌细胞凋亡更少。此外，我们发现大多数移植的转导HIF-1α-NIS的BMSCs分化为内皮细胞，并在梗死区域构建了新的血管。微型PET/CT成像显示，在早期时间点（移植后2周）代谢活性显著增加，并持续增加（4周），这由（18）F-FDG摄取所示。超声心动图显示，2周时心脏功能无改善，4周时有轻微改善。这项研究表明，（18）F-FDG微型PET/CT在评估早期治疗效果方面比超声心动图更有用。
