Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: Oncogenic transformation with epithelial-mesenchymal transition

Satoshi Nori, Yohei Okada, Soraya Nishimura, Takashi Sasaki, Go Itakura, Yoshiomi Kobayashi, Francois Renault-Mihara, Atsushi Shimizu, Ikuko Koya, Rei Yoshida, Jun Kudo, Masato Koike, Yasuo Uchiyama, Eiji Ikeda, Yoshiaki Toyama, Masaya Nakamura, Hideyuki Okano

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)360-373
Number of pages14
JournalStem Cell Reports
Volume4
Issue number3
DOIs
Publication statusPublished - 2015 Mar 10

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Induced Pluripotent Stem Cells
Epithelial-Mesenchymal Transition
Cell- and Tissue-Based Therapy
Stem cells
Spinal Cord Injuries
Tumors
Clone Cells
Safety
Nestin
Neoplasms
Gene Expression Profiling
Fibroblasts
Transgenes
Synapses
Transplantation
Chemical activation
Observation
Tissue Donors
Recovery
Skin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics

Cite this

Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model : Oncogenic transformation with epithelial-mesenchymal transition. / Nori, Satoshi; Okada, Yohei; Nishimura, Soraya; Sasaki, Takashi; Itakura, Go; Kobayashi, Yoshiomi; Renault-Mihara, Francois; Shimizu, Atsushi; Koya, Ikuko; Yoshida, Rei; Kudo, Jun; Koike, Masato; Uchiyama, Yasuo; Ikeda, Eiji; Toyama, Yoshiaki; Nakamura, Masaya; Okano, Hideyuki.

In: Stem Cell Reports, Vol. 4, No. 3, 10.03.2015, p. 360-373.

Research output: Contribution to journalArticle

Nori, S, Okada, Y, Nishimura, S, Sasaki, T, Itakura, G, Kobayashi, Y, Renault-Mihara, F, Shimizu, A, Koya, I, Yoshida, R, Kudo, J, Koike, M, Uchiyama, Y, Ikeda, E, Toyama, Y, Nakamura, M & Okano, H 2015, 'Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: Oncogenic transformation with epithelial-mesenchymal transition', Stem Cell Reports, vol. 4, no. 3, pp. 360-373. https://doi.org/10.1016/j.stemcr.2015.01.006
Nori, Satoshi ; Okada, Yohei ; Nishimura, Soraya ; Sasaki, Takashi ; Itakura, Go ; Kobayashi, Yoshiomi ; Renault-Mihara, Francois ; Shimizu, Atsushi ; Koya, Ikuko ; Yoshida, Rei ; Kudo, Jun ; Koike, Masato ; Uchiyama, Yasuo ; Ikeda, Eiji ; Toyama, Yoshiaki ; Nakamura, Masaya ; Okano, Hideyuki. / Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model : Oncogenic transformation with epithelial-mesenchymal transition. In: Stem Cell Reports. 2015 ; Vol. 4, No. 3. pp. 360-373.
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