Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China.
Biomaterials. 2019 Mar;197:229-243. doi: 10.1016/j.biomaterials.2018.05.053. Epub 2018 May 30.
Endothelial progenitor cell (EPC)-based therapy has brought potential benefits to stroke patients as an important restorative therapeutics. However, its efficacy is limited by poor migration and survival ability. Here, we found out that hif-prolyl hydroxylase 2 (PHD2) silencing could enhance the migration and survival ability of EPCs which could improve the therapy efficacy for ischemic stroke. We successfully developed a siRNA delivery system, which could achieve siRNA delivery and EPCs tracking with magnetic resonance imaging (MRI) simultaneously. Besides, combining MRI and bioluminescence imaging (BLI), we successfully observed full temporal profile of EPCs dynamics in vivo. Furthermore, we found out that PHD2 silencing in EPCs elevated the expression of C-X-C chemokine receptor type 4 (CXCR4) and hypoxia-inducible factor 1α (HIF-1α), which enhanced the migration and survival ability of EPCs respectively. Significantly decreased infarct volume, functional deficits and increased fractional anisotrophy (FA) value, fiber counts were observed in the siPHD2-EPCs (EPCs transfected with siRNA targeting PHD2) group. What's more, higher level of BNDF, CD31, DCX, NeuN and MBP were also observed in the siPHD2-EPCs group. Altogether, our study provides an effective method to improve EPC-based therapy efficacy for ischemic stroke.
基于内皮祖细胞 (EPC) 的治疗为中风患者带来了潜在的益处，是一种重要的修复治疗方法。然而，其疗效受到迁移和生存能力差的限制。在这里，我们发现沉默低氧诱导因子脯氨酰羟化酶 2 (PHD2) 可以增强 EPC 的迁移和生存能力，从而提高缺血性中风的治疗效果。我们成功开发了一种 siRNA 递送系统，该系统可以同时实现 siRNA 的递送和 EPC 的跟踪磁共振成像 (MRI)。此外，通过结合磁共振成像和生物发光成像 (BLI)，我们成功地在体内观察到了 EPC 动力学的完整时间过程。此外，我们发现沉默 EPC 中的 PHD2 可上调 C-X-C 趋化因子受体 4 (CXCR4) 和缺氧诱导因子 1α (HIF-1α) 的表达，分别增强了 EPC 的迁移和生存能力。在 siPHD2-EPCs（转染靶向 PHD2 的 siRNA 的 EPCs）组中，观察到梗死体积明显减小、功能缺陷减少，分数各向异性 (FA) 值增加，纤维计数增加。更重要的是，在 siPHD2-EPCs 组中还观察到更高水平的 BDNF、CD31、DCX、NeuN 和 MBP。总之，我们的研究为提高基于 EPC 的缺血性中风治疗效果提供了一种有效的方法。
