Tumorigenic risk of human induced pluripotent stem cell explants cultured on mouse SNL76/7 feeder cells

The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselv...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2014-10, Vol.453 (3), p.668-673
Main Authors: Kamada, Mizuna, Mitsui, Youji, Kumazaki, Tsutomu, Kawahara, Yuta, Matsuo, Taira, Takahashi, Tomoko
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Animals
Carcinogenesis
Cell Line
EMBRYOS
Feeder Cells
FIBROBLASTS
Gene Expression Profiling
GENES
HAZARDS
HUMAN POPULATIONS
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
MEDICINE
MICE
Mice, SCID
MITOMYCIN
Neoplasms, Experimental - pathology
SARCOMAS
Stem Cell Transplantation
STEM CELLS
TRANSPLANTS
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Summary:The potential for tumor formation from transplanted human induced pluripotent stem cell (hiPSC) derivatives represents a high risk in their application to regenerative medicine. We examined the genetic origin and characteristics of tumors, that were formed when 13 hiPSC lines, established by ourselves, and 201B7 hiPSC from Kyoto University were transplanted into severe combined immune-deficient (SCID) mice. Though teratomas formed in 58% of mice, five angiosarcomas, one malignant solitary fibrous tumor and one undifferentiated pleomorphic sarcoma formed in the remaining mice. Three malignant cell lines were established from the tumors, which were derived from mitomycin C (MMC)-treated SNL76/7 (MMC-SNL) feeder cells, as tumor development from fusion cells between MMC-SNL and hiPSCs was negative by genetic analysis. While parent SNL76/7 cells produced malignant tumors, neither MMC-SNL nor MMC-treated mouse embryo fibroblast (MEF) produced malignant tumors. When MMC-SNL feeder cells were co-cultured with hiPSCs, growing cell lines were generated, that expressed genes similar to the parent SNL76/7 cells. Thus, hiPSCs grown on MMC-SNL feeder cells have a high risk of generating feeder-derived malignant tumors. The possible mechanism(s) of growth restoration and the formation of multiple tumor types are discussed with respect of the interactions between MMC-SNL and hiPSC.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2014.10.009