Okano Hideyuki
Department of Physiology, Keio University School of Medicine.
Rinsho Shinkeigaku. 2009 Nov;49(11):825-6. doi: 10.5692/clinicalneurol.49.825.
Induced pluripotent stem (iPS) cells are pluripotent stem cells directly reprogrammed from cultured mouse fibroblast by introducing Oct3/4, Sox2, c-Myc, and Klf4. Cells obtained using this technology, which allows the ethical issues and immunological rejection associated with embryonic stem (ES) cells to be avoided, might be a clinically useful source for cell replacement therapies. We found that secondary neurospheres (SNSs) generated from various mouse iPS cell showed their neural differentiation capacity and teratoma formation after transplantation into the brain of immunodeficient NOD/SCID mice. We found that origin (source of somatic cells) of the iPS cells are the crucial determinant for the potential tumorigenicity of iPS-derived neural stem/progenitor cells and that their tumorigenicity results from the persistent presence of undifferentiated cells within the SNSs. Surprisingly, SNSs derived from c-Myc minus iPS cells generated without drug selection showed robust tumorigenesis, in spite of their potential to contribute adult chimeric mice without tumor formation. Furthermore, we examined whether the transplantation of non-tumorigenic Nanog-iPS-derived SNSs into mouse spinal cord injury (SCI) model could promote locomotor function recovery. As a result, we found that properly pre-evaluated iPS clone-derived neural stem/progenitor cells may be a promising cell source for future transplantation therapy of SCI.
诱导多能干细胞(iPS细胞)是通过导入Oct3/4、Sox2、c-Myc和Klf4从培养的小鼠成纤维细胞直接重编程得到的多能干细胞。利用这项技术获得的细胞可以避免与胚胎干细胞(ES细胞)相关的伦理问题和免疫排斥反应,可能是细胞替代疗法临床上有用的细胞来源。我们发现,从各种小鼠iPS细胞产生的次级神经球(SNSs)在移植到免疫缺陷的NOD/SCID小鼠脑内后显示出其神经分化能力和畸胎瘤形成。我们发现iPS细胞的起源(体细胞来源)是iPS衍生的神经干细胞/祖细胞潜在致瘤性的关键决定因素,并且它们的致瘤性是由于SNSs中未分化细胞的持续存在。令人惊讶的是,在没有药物选择的情况下产生的c-Myc缺失的iPS细胞衍生的SNSs尽管有能力形成无肿瘤的成年嵌合小鼠,但仍显示出强大的肿瘤发生能力。此外,我们研究了将无致瘤性的Nanog-iPS衍生的SNSs移植到小鼠脊髓损伤(SCI)模型中是否能促进运动功能恢复。结果,我们发现经过适当预评估的iPS克隆衍生的神经干细胞/祖细胞可能是未来SCI移植治疗的有前景的细胞来源。