Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Cytotherapy. 2013 Dec;15(12):1484-97. doi: 10.1016/j.jcyt.2013.06.010.
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.
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 × 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.
Taken together, immortalized hfBMSCs represent a reliable and safe source of MSCs for further clinical translational study.
癌症是当今世界面临的最大健康挑战之一，每年有超过 1000 万例新癌症病例。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用于抗肿瘤治疗的自杀基因的潜在传递候选物。然而，成人 MSCs 在体外的供应不稳定和寿命短限制了这种治疗潜力。在本研究中，我们旨在评估通过猿猴病毒 40（SV40-hfBMSCs）使人类胎儿骨髓来源的间充质基质细胞永生化是否可以成为自杀基因治疗临床应用的 MSC 的稳定来源。
SV40 和单纯疱疹病毒胸苷激酶-IRES-绿色荧光蛋白（TK-GFP）的转导不会导致 hfBMSCs 的干细胞特性发生显著变化。在存在前药更昔洛韦的情况下，SV40-TK-hfBMSCs 在体外和裸鼠中携带已被荧光素酶和 GFP 转导的人前列腺癌细胞 DU145 和 PC3 中显示出抗肿瘤作用，用于通过体内活体成像系统（IVIS 200 成像系统； Caliper Life Sciences）进行活体成像评估。重复注射低剂量（1×10^6 个细胞/kg）的 SV40-TK-hfBMSCs 与先前报道的一样有效，并且不会在多个器官中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 不会诱导来自健康成年人的淋巴细胞的显著增殖。
综上所述，永生化 hfBMSCs 代表了一种可靠和安全的 MSC 来源，可用于进一步的临床转化研究。
