Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition

被引：200

作者：

Nori, Satoshi ^{[1
,2
]}

Okada, Yohei ^{[2
,3
]}

Nishimura, Soraya ^{[1
,2
]}

Sasaki, Takashi ^{[4
,5
]}

Itakura, Go ^{[1
,2
]}

Kobayashi, Yoshiomi ^{[1
,2
]}

Renault-Mihara, Francois ^{[1
,2
]}

Shimizu, Atsushi ^{[6
]}

Koya, Ikuko ^{[2
]}

Yoshida, Rei ^{[1
]}

Kudoh, Jun ^{[7
]}

Koike, Masato ^{[8
]}

Uchiyama, Yasuo ^{[8
]}

Ikeda, Eiji ^{[9
,10
]}

Toyama, Yoshiaki ^{[1
]}

Nakamura, Masaya ^{[1
]}

Okano, Hideyuki ^{[2
]}

机构：

[1] Keio Univ, Sch Med, Dept Orthoped Surg, Shinjuku Ku, Tokyo 1608582, Japan

[2] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, Tokyo 1608582, Japan

[3] Keio Univ, Sch Med, Kanrinmaru Project, Shinjuku Ku, Tokyo 1608582, Japan

[4] Keio Univ, Sch Med, Ctr Integrated Med Res, Shinjuku Ku, Tokyo 1608582, Japan

[5] Keio Univ, Sch Med, Dept Dermatol, Shinjuku Ku, Tokyo 1608582, Japan

[6] Keio Univ, Sch Med, Dept Mol Biol, Shinjuku Ku, Tokyo 1608582, Japan

[7] Keio Univ, Sch Med, Lab Gene Med, Shinjuku Ku, Tokyo 1608582, Japan

[8] Juntendo Univ, Grad Sch Med, Dept Cell Biol & Neurosci, Bunkyo Ku, Tokyo 1138421, Japan

[9] Keio Univ, Sch Med, Dept Pathol, Shinjuku Ku, Tokyo 1608582, Japan

[10] Yamaguchi Univ, Grad Sch Med, Dept Pathol, Ube, Yamaguchi 7558505, Japan

来源：

STEM CELL REPORTS | 2015年 / 4卷 / 03期

基金：

日本科学技术振兴机构; 日本学术振兴会;

关键词：

PLURIPOTENT STEM-CELLS; NEURAL STEM/PROGENITOR CELLS; PROMOTE LOCOMOTOR RECOVERY; FUNCTIONAL RECOVERY; MOTONEURON PROGENITORS; HUMAN FIBROBLASTS; HUMAN GLIOMAS; CANCER-CELLS; MOUSE MODEL; RNA-SEQ;

D O I：

10.1016/j.stemcr.2015.01.006

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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.

引用

页码：360 / 373

页数：14

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