Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury
Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury
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DOI：
10.1002/sctm.18-0096
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发表时间：
2019-03-01
影响因子：
6
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Kojima, Kota;Miyoshi, Hiroyuki;Okano, Hideyuki
肿瘤发生是人类干/祖细胞移植治疗亚急性脊髓损伤（SCI）领域需要解决的重要问题。当某些“致瘤”细胞系被移植到SCI小鼠模型的脊髓中时，运动功能有初步的改善，随后是继发于肿瘤生长的影响的突然恶化。移植后相当大比例的移植细胞保持未分化状态，被认为会增加肿瘤发生的风险。在这项研究中，使用慢病毒载体，我们介绍了单纯疱疹病毒1型胸苷激酶（HSVtk）基因到人诱导多能干细胞衍生的神经干/祖细胞（hiPSC-NS/PC）线，已知进行致瘤性转化。这种方法能够选择性消融未成熟的增殖细胞，从而防止随后的肿瘤形成。在体外，HSVtk系统成功地消融未成熟的增殖神经细胞，同时保留成熟的有丝分裂后神经元细胞。在体内移植到免疫缺陷（非肥胖糖尿病-严重联合免疫缺陷）小鼠的损伤脊髓后观察到类似的结果。切除增殖细胞对移植后恢复的运动功能具有保护作用，同时保护脊髓免受有害肿瘤生长的影响。这些结果表明，在干细胞治疗过程中，自杀基因在对抗肿瘤发生方面具有潜在的前景。该系统允许预防和治疗hiPSC-NS/PC移植后的肿瘤发生，而不牺牲改善的运动功能。
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function.