Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition.
Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition.
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DOI：
10.1016/j.stemcr.2015.01.006
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发表时间：
2015-03-10
影响因子：
5.9
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Nori, Satoshi;Okada, Yohei;Nishimura, Soraya;Sasaki, Takashi;Itakura, Go;Kobayashi, Yoshiomi;Renault-Mihara, Francois;Shimizu, Atsushi;Koya, Ikuko;Yoshida, Rei;Kudoh, Jun;Koike, Masato;Uchiyama, Yasuo;Ikeda, Eiji;Toyama, Yoshiaki;Nakamura, Masaya;Okano, Hideyuki
之前，我们描述了来自人诱导多能干细胞（iPSC）克隆201 B7的神经球（NS）在脊髓损伤（SCI）小鼠模型中的安全性和治疗潜力。然而，关于基于iPSC的细胞疗法的几个安全性问题仍然没有得到解决。在这里，我们研究了另一个iPSC克隆253 G1，我们通过将OCT 4，SOX 2和KLF 4转导到从提供201 B7克隆的同一供体收集的成人皮肤成纤维细胞中建立。移植后47天，移植的253 G1-NS存活，分化为三个神经谱系，并促进功能恢复，伴随着刺激的突触形成。然而，长期观察（长达103天）显示运动功能恶化伴随着肿瘤形成。肿瘤由巢蛋白+未分化的神经细胞组成，并表现出OCT 4转基因的激活。转录组分析显示，增强的间充质转化可能有助于移植细胞衍生的肿瘤的进展。移植的iPSC（253 G1）衍生的神经球在长期观察后形成肿瘤OCT 4转基因的激活与肿瘤形成潜在相关肿瘤进展可能是由移植细胞的间充质转化引起的应选择无整合的iPSC以避免转基因诱导的肿瘤发生以前，Okano及其同事报道了诱导多能干细胞（iPSC）衍生的神经球对脊髓损伤的治疗潜力。然而，有关iPSC治疗的安全性问题仍未得到解决。在这篇文章中，他们表明，移植的人iPSC（253 G1）衍生的神经球在长期观察后形成了未分化的神经肿瘤。肿瘤表现出OCT 4转基因的激活和增强的间充质转化。应选择无整合的iPSC以避免转基因诱导的肿瘤发生。
Previously, we described the safety and therapeutic potential of neurospheres (NSs) derived from a human induced pluripotent stem cell (iPSC) clone, 201B7, in a spinal cord injury (SCI) mouse model. However, several safety issues concerning iPSC-based cell therapy remain unresolved. Here, we investigated another iPSC clone, 253G1, that we established by transducing OCT4, SOX2, and KLF4 into adult human dermal fibroblasts collected from the same donor who provided the 201B7 clone. The grafted 253G1-NSs survived, differentiated into three neural lineages, and promoted functional recovery accompanied by stimulated synapse formation 47 days after transplantation. However, long-term observation (for up to 103 days) revealed deteriorated motor function accompanied by tumor formation. The tumors consisted of Nestin+ undifferentiated neural cells and exhibited activation of the OCT4 transgene. Transcriptome analysis revealed that a heightened mesenchymal transition may have contributed to the progression of tumors derived from grafted cells. Grafted iPSC (253G1)-derived neurospheres formed tumors after long-term observation Activation of the OCT4 transgene is potentially related to tumor formation Tumor progression may have been caused by mesenchymal transition of grafted cells Integration-free iPSCs should be chosen to avoid transgene-induced tumorigenesis Previously, Okano and colleagues reported the therapeutic potential of induced pluripotent stem cell (iPSC)-derived neurospheres for spinal cord injury. However, safety issues concerning iPSC-based therapy remain unresolved. In this article, they show that grafted human iPSC (253G1)-derived neurospheres formed undifferentiated neural tumors after long-term observation. The tumors exhibited activation of the OCT4 transgene and a heightened mesenchymal transition. Integration-free iPSCs should be chosen to avoid transgene-induced tumorigenesis.
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影响因子：
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