Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition
| Autor: | Takashi Sasaki, Yasuo Uchiyama, Yoshiaki Toyama, Masaya Nakamura, Francois Renault-Mihara, Ikuko Koya, Atsushi Shimizu, Satoshi Nori, Go Itakura, Yohei Okada, Yoshiomi Kobayashi, Rei Yoshida, Eiji Ikeda, Hideyuki Okano, Soraya Nishimura, Jun Kudoh, Masato Koike |
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| Rok vydání: | 2015 |
| Předmět: |
Epithelial-Mesenchymal Transition
Cell Survival Induced Pluripotent Stem Cells Clone (cell biology) Biology Biochemistry Article Cell therapy Kruppel-Like Factor 4 Mice SOX2 Neurosphere Genetics Animals Cluster Analysis Humans Cell Lineage Epithelial–mesenchymal transition Induced pluripotent stem cell lcsh:QH301-705.5 Spinal Cord Injuries Neurons lcsh:R5-920 Gene Expression Profiling Mesenchymal stem cell Computational Biology Cell Differentiation Cell Biology Transplantation Disease Models Animal Cell Transformation Neoplastic lcsh:Biology (General) Astrocytes Immunology Cancer research Heterografts lcsh:Medicine (General) Transcriptome Neuroglia Signal Transduction Stem Cell Transplantation Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 4, Iss 3, Pp 360-373 (2015) |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2015.01.006 |
| Popis: | Summary 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. Graphical Abstract Highlights • 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. |
| Databáze: | OpenAIRE |
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