Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain.
Induced pluripotent stem (iPS) cells may provide cures for various neurological diseases. However, undifferentiated iPS cells have high tumorigenicity, and evaluation of the cells fates, especially in pathologic condition model, is needed. In this study, we demonstrated the effect of ischemic condition to undifferentiated iPS cells fates in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells were characterized with immunofluorescent staining. The iPS cells (5 × 10⁵) were injected into ipsilateral striatum and cortex after 24 h of MCAO. Histological analysis was performed from 3 to 28 days after cell transplantation. iPS cells in ischemic brain formed teratoma with higher probability (p < 0.05) and larger volume (p < 0.01) compared with those in intact brain. Among the four transcriptional factors to produce iPS cells, c-Myc, Oct3/4, and Sox2 strongly expressed in iPS-derived tumors in ischemic brain (p < 0.01). Additionally, expression of matrix metalloproteinase-9 (MMP-9) and phosphorylated vascular endothelial growth factor receptor2 (phospho-VEGFR2) were significantly increased in iPS-derived tumors in the ischemic brain (p < 0.05). These results suggest that the transcriptional factors might increase expression of MMP-9 and activate VEGFR2, promoting teratoma formation in the ischemic brain. We strongly propose that the safety of iPS cells should be evaluated not only in normal condition, but also in a pathologic, disease model.
Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Toru
T
Yamashita
Hiromi
H
Kawai
Fengfeng
F
Tian
Yasuyuki
Y
Ohta
Koji
K
Abe
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D050814:Octamer Transcription Factor-3; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9