Immortalized human fetal bone marrow-derived mesenchymal stromal cell expressing suicide gene for anti-tumor therapy in vitro and in vivo
Immortalized human fetal bone marrow-derived mesenchymal stromal cell expressing suicide gene for anti-tumor therapy in vitro and in vivo
复制标题
DOI：
10.1016/j.jcyt.2013.06.010
复制
发表时间：
2013-12-01
期刊：
影响因子：
4.5
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Lee, Wayne Y. W.;Zhang, Ting;Li, Gang
背景的目标。癌症是当今世界面临的最大健康挑战之一，每年有1000万新发癌症病例。间充质基质细胞（MSCs）的自我更新、肿瘤归巢能力和低免疫原性使其成为抗肿瘤治疗自杀基因的潜在递送候选者。然而，体外成人间充质干细胞的供应不稳定和寿命短限制了这种治疗潜力。在这项研究中，我们旨在评估用猴病毒40 （SV40-hfBMSCs）永生化人胎骨髓间充质间质细胞是否可以作为临床自杀基因治疗应用的MSCs的稳定来源。方法与结果。SV40和单纯疱疹病毒胸苷激酶- ires -绿色荧光蛋白（TK-GFP）的转导没有引起hfBMSCs干细胞特性的显著变化。SV40-TK-hfBMSCs在前药更昔洛韦存在下的抗肿瘤作用在体外和携带人前列腺癌细胞、DU145和PC3的裸鼠中得到了证明，用荧光素酶和GFP转导PC3，通过活体成像系统（IVIS 200成像系统；Caliper Life Sciences）进行成像评估。重复注射低剂量（1 × 10(6)个细胞/kg） SV40-TK-hfBMSCs与先前报道的一样有效，并且在多个器官中没有引起可观察到的有害副作用。混合淋巴细胞反应表明，SV40-TK-hfBMSCs不诱导健康成人分离淋巴细胞的显著增殖。结论。综上所述，永生化的骨髓间充质干细胞为进一步的临床转化研究提供了可靠和安全的骨髓间充质干细胞来源。
Background aims. Cancer is one of the greatest health challenges facing the world today with >10 million new cases of cancer every year. The self-renewal, tumor-homing ability and low immunogenicity of mesenchymal stromal cells (MSCs) make them potential delivery candidates for suicide genes for anti-tumor therapy. However, unstable supply and short life span of adult MSCs in vitro have limited this therapeutic potential. In this study, we aimed to evaluate if immortalization of human fetal bone marrow-derived mesenchymal stromal cells by simian virus 40 (SV40-hfBMSCs) could be a stable source of MSCs for clinical application of suicide gene therapy. Methods and Results. Transduction of SV40 and herpes simplex virus thymidine kinase-IRES-green fluorescent protein (TK-GFP) did not cause significant change in the stem cell properties of hfBMSCs. The anti-tumor effect of SV40-TK-hfBMSCs in the presence of the prodrug ganciclovir was demonstrated in vitro and in nude mice bearing human prostate cancer cells, DU145 and PC3, which had been transduced with luciferase and GFP for imaging evaluation by an in vivo live imaging system (IVIS 200 imaging system; Caliper Life Sciences). Repeated injection of low doses (1 x 10(6) cells/kg) of SV40-TK-hfBMSCs was as effective as previously reported and did not cause observable harmful side effects in multiple organs. Mixed lymphocyte reaction showed that SV40-TK-hfBMSCs did not induce significant proliferation of lymphocytes isolated from healthy adults. Conclusions. Taken together, immortalized hfBMSCs represent a reliable and safe source of MSCs for further clinical translational study.