Biosafety Assessment of Human Mesenchymal Stem Cells Engineered by Hybrid Baculovirus Vectors

被引:50
作者
Chen, Chi-Yuan [1 ]
Wu, Hsiao-Hsuan [1 ]
Chen, Chih-Ping [2 ]
Chern, Schu-Rern [2 ]
Hwang, Shiaw-Min [3 ]
Huang, Shiu-Feng [4 ]
Lo, Wen-Hsin [1 ]
Chen, Guan-Yu [1 ]
Hu, Yu-Chen [1 ]
机构
[1] Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu 300, Taiwan
[2] MacKay Mem Hosp, Div Genet, Dept Obstet & Gynecol, Taipei 104, Taiwan
[3] Food Ind Res & Dev Inst, Bioresource Collect & Res Ctr, Hsinchu 300, Taiwan
[4] Natl Hlth Res Inst, Div Mol & Genom Med, Miaoli 350, Taiwan
关键词
baculovirus; mesenchymal stem cell; biosafety; sustained expression; hybrid vector; NUCLEAR POLYHEDROSIS-VIRUS; MAMMALIAN-CELLS; TRANSGENE EXPRESSION; STROMAL CELLS; GENE-THERAPY; IN-VITRO; HEPATOCELLULAR-CARCINOMA; CHROMOSOMAL INTEGRATION; IMMUNE-RESPONSES; CANCER-THERAPY;
D O I
10.1021/mp100368d
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Mesenchymal stem cells (MSCs) hold promise for cell therapy, and implantation of MSCs engineered with a baculovirus transiently expressing the growth factor can augment the bone repair. To prolong the baculovirus-mediated transgene expression, we developed hybrid baculovirus vectors exploiting the FLP/Frt-mediated recombination for circular episome formation. Transduction of human MSCs with the hybrid baculovirus vectors harboring the osteoinductive bmp2 gene substantially extended the BMP2 expression and improved the cellular osteogenic differentiation. To confirm the potential in the clinical setting, the present study evaluated the biosafety profile of human MSCs engineered by the hybrid vectors. We unraveled that transduction of MSCs with the hybrid baculovirus vectors slightly impeded the cell proliferation after transduction, probably due to the perturbation of cellular gene expression and induction of innate responses. Nonetheless, the hybrid baculovirus vectors did not compromise the cell viability and cellular differentiation. No transgene integration into the host chromosome and disruption of the karyotype of the MSCs were observed. Additionally, no upregulation of proto-oncogenes or downregulation of tumor suppressor genes occurred in the MSCs transduced with the hybrid baculovirus vectors. Neither did the transduced MSCs induce tumor formation in nude mice. This study not only supported the safety of MSCs for cell therapy but also implicated the potential of the human MSCs engineered by the hybrid baculovirus vectors for their applications in clinical scenarios necessitating sustained transgene expression.
引用
收藏
页码:1505 / 1514
页数:10
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