TY - JOUR
T1 - Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model
T2 - Oncogenic transformation with epithelial-mesenchymal transition
AU - Nori, Satoshi
AU - Okada, Yohei
AU - Nishimura, Soraya
AU - Sasaki, Takashi
AU - Itakura, Go
AU - Kobayashi, Yoshiomi
AU - Renault-Mihara, Francois
AU - Shimizu, Atsushi
AU - Koya, Ikuko
AU - Yoshida, Rei
AU - Kudoh, Jun
AU - Koike, Masato
AU - Uchiyama, Yasuo
AU - Ikeda, Eiji
AU - Toyama, Yoshiaki
AU - Nakamura, Masaya
AU - Okano, Hideyuki
N1 - Funding Information:
We thank A. Iwanami, S. Kaneko, K. Fujiyoshi, O. Tsuji, A. Yasuda, Y. Takahashi, S. Kawabata, Y. Nishiyama, T. Iida, S. Shibata, T. Harada, S. Miyao, and H.J. Okano for technical assistance and scientific discussions, and H. Saya, M. Ko, M. Jakt, and K. Horiuchi for critical readings of the manuscript. We also thank S. Yamanaka and M. Nakagawa for the human iPSC clones (253G1 and 201B7). The p-STAT3, p-ERK1/2, and p-AKT antibodies were kindly provided by N. Onishi. This work was supported by grants from the JST-CIRM collaborative program; Grants-in-Aid for Scientific Research from JSPS and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) ; Research Center Network for Realization of Regenerative Medicine from by the Japan Science and Technology Agency (JST) ; the Kanrinmaru Project ( Keio University ); Research Fellowships for Young Scientists from the Japan Society for the Promotion of Science ; Keio Gijuku Academic Development Funds ; and a Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the MEXT .
Publisher Copyright:
© 2015 The Authors.
PY - 2015/3/10
Y1 - 2015/3/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stemcr.2015.01.006
DO - 10.1016/j.stemcr.2015.01.006
M3 - Article
C2 - 25684226
AN - SCOPUS:84924574219
VL - 4
SP - 360
EP - 373
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 3
ER -