Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Cell Transplant. 2012;21(4):763-71. doi: 10.3727/096368911X623907. Epub 2012 Feb 2.
This study evaluated the tumorigenesis risk of induced pluripotent stem (iPS) cells after transplantation into the cochlea. One mouse embryonic stem (ES) cell line and three mouse iPS cell lines, one derived from adult mouse tail-tip fibroblasts (TTFs) and two from mouse embryonic fibroblasts (MEFs), were neurally induced by stromal cell-inducing activity. Before transplantation, the efficiency of neural induction and the proportion of residual undifferentiated cells were evaluated using immunocytochemistry, and no significant differences were observed in the ratios of colonies expressing βIII tubulin, nestin, or octamer (Oct)3/4. Four weeks after transplantation into the cochleae of neonatal mice, the number of surviving transplants of TTF-derived iPS cells generated by retroviral infection was significantly higher than those of MEF-derived iPS cells generated by plasmid transfection. Teratoma formation was identified in one of five cochleae transplanted with TTF-derived iPS cells. However, no significant differences were found in the cell proliferation activity or the extent of differentiation into mature neurons among the cell lines. These findings emphasize the necessity of selecting appropriate iPS cell lines and developing methods to eliminate undifferentiated cells after neural induction, in order to establish safe iPS cell-based therapy for the inner ear.
本研究评估了诱导多能干细胞（iPS 细胞）移植到耳蜗后的肿瘤发生风险。通过基质细胞诱导活性对 1 个小鼠胚胎干细胞（ES）系和 3 个小鼠 iPS 细胞系进行神经诱导，其中 1 个来源于成年小鼠尾尖成纤维细胞（TTF），另外 2 个来源于小鼠胚胎成纤维细胞（MEF）。移植前，通过免疫细胞化学评估神经诱导效率和残余未分化细胞的比例，表达βIII 微管蛋白、巢蛋白或八聚体（Oct）3/4 的克隆比例无显著差异。将 TTF 来源的 iPS 细胞通过逆转录病毒感染移植到新生小鼠耳蜗 4 周后，移植的存活细胞数量明显高于 MEF 来源的 iPS 细胞通过质粒转染生成的数量。在移植 TTF 来源的 iPS 细胞的 5 个耳蜗中有 1 个形成了畸胎瘤。然而，在细胞系之间，细胞增殖活性或分化为成熟神经元的程度没有显著差异。这些发现强调了选择合适的 iPS 细胞系和开发方法来消除神经诱导后未分化细胞的必要性，以建立用于内耳的安全 iPS 细胞为基础的治疗方法。
