Liu Ying, Fan Zhigang, Li Kang, Deng Fei, Xiong Yunfan, Liang Meixin, Ge Jian
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China.
The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650031, P.R. China.
Int J Mol Med. 2017 Sep;40(3):801-813. doi: 10.3892/ijmm.2017.3058. Epub 2017 Jul 6.
The pathogenesis of Rb1 gene inactivation indicates that gene therapy could be a promising treatment for retinoblastoma. An appropriate gene transfer system is the basis for successful gene therapy; however, little attention has been given to an effective gene transfer system for retinoblastoma therapy in previous studies. This study was designed to provide an optimized transgene system for WERI‑Rb1 cells (W-RBCs). Green fluorescent protein (GFP) was adopted as a reporter. Four classic viral vectors based on retroviruses, recombinant adeno-associated viruses (rAAV2, rAAV2/1), lentiviruses (LVs) and a novel non-viral vector X-treme HP reagent were adopted for W-RBC gene transfection. The efficacy and cytotoxicity were comprehensively compared among the different vectors through GFP expression and the trypan blue exclusion test. Furthermore, the serum and cell culture status were also optimized for better transfection. Cells transfected by rAAV2/1 expressed more GFP protein and exhibited less staining with trypan blue, compared to the rAAV2 counterpart. However, in comparison to the retroviral group, both the rAAV2/1 and LV groups had considerably less GFP+ cells. Interestingly, the X-treme HP presented a similar GFP transfection capacity to the retroviral vector, but with a much lower cytotoxicity. Furthermore, there were more GFP+ cells in a suspended condition than that in an adherent culture. Moreover, cells in a serum-positive system expressed more GFP, while cells in a serum-free system showed lower GFP expression and higher cytotoxicity. In conclusion, the retroviral vector and the X-treme HP are effective for W-RBC gene transfection, while the X-treme HP is more preferable due to its lower cytotoxicity. Moreover, the suspended cell culture system is superior to the adherent system, and the serum protects cell viability and facilitates the gene transfection of W-RBCs. This study presents an effective, convenient, and low toxic transfection system for gene delivery in W-RBCs and provides a promising system for further gene therapy of retinoblastoma.
Rb1基因失活的发病机制表明基因治疗可能是视网膜母细胞瘤的一种有前景的治疗方法。合适的基因传递系统是成功进行基因治疗的基础;然而,以往的研究很少关注用于视网膜母细胞瘤治疗的有效基因传递系统。本研究旨在为WERI-Rb1细胞(W-RBCs)提供一种优化的转基因系统。采用绿色荧光蛋白(GFP)作为报告基因。采用四种基于逆转录病毒的经典病毒载体、重组腺相关病毒(rAAV2、rAAV2/1)、慢病毒(LVs)和一种新型非病毒载体X-treme HP试剂对W-RBC进行基因转染。通过GFP表达和台盼蓝排斥试验全面比较不同载体之间的转染效率和细胞毒性。此外,还对血清和细胞培养条件进行了优化以实现更好的转染。与rAAV2相比,rAAV2/1转染的细胞表达更多的GFP蛋白,并且台盼蓝染色更少。然而,与逆转录病毒组相比,rAAV2/1组和LV组的GFP+细胞都明显更少。有趣的是,X-treme HP表现出与逆转录病毒载体相似的GFP转染能力,但细胞毒性要低得多。此外,悬浮状态下的GFP+细胞比贴壁培养时更多。而且,血清阳性系统中的细胞表达更多的GFP,而无血清系统中的细胞GFP表达较低且细胞毒性较高。总之,逆转录病毒载体和X-treme HP对W-RBC基因转染有效,而X-treme HP因其较低的细胞毒性更具优势。此外,悬浮细胞培养系统优于贴壁系统,血清可保护细胞活力并促进W-RBC的基因转染。本研究为W-RBC的基因递送提供了一种有效、便捷且低毒的转染系统,并为视网膜母细胞瘤的进一步基因治疗提供了一个有前景的系统。