title: Fail-Safe Therapy by Gamma-Ray Irradiation Against Tumor Formation by Human-Induced Pluripotent Stem Cell-Derived Neural Progenitors.
abstract: Cell replacement therapy holds great promise for Parkinson's disease (PD), but residual undifferentiated cells and immature neural progenitors in the therapy may cause tumor formation. Although cell sorting could effectively exclude these proliferative cells, from the viewpoint of clinical application, there exists no adequate coping strategy in the case of their contamination. In this study, we analyzed a component of proliferative cells in the grafts of human-induced pluripotent stem cell-derived neural progenitors and investigated the effect of radiation therapy on tumor formation. In our differentiating protocol, analyses of neural progenitors (day 19) revealed that the proliferating cells expressed early neural markers (SOX1, PAX6) or a dopaminergic neuron progenitor marker (FOXA2). When grafted into the rat striatum, these immature neurons gradually became postmitotic in the brain, and the rosette structures disappeared at 14 weeks. However, at 4-8 weeks, the SOX1(+)PAX6(+) cells formed rosette structures in the grafts, suggesting their tumorigenic potential. Therefore, to develop a fail-safe therapy against tumor formation, we investigated the effect of radiation therapy. At 4 weeks posttransplantation, when KI67(+) cells comprised the highest ratio, radiation therapy with (137)Cs Gammacell Exactor for tumor-bearing immunodeficient rats showed a significant decrease in graft volume and percentage of SOX1(+)KI67(+) cells in the graft, thus demonstrating the preventive effect of gamma-ray irradiation against tumorigenicity. These results give us critical criteria for the safety of future cell replacement therapy for PD.
authors.affiliation: 1 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan .|2 Department of Signal Transductions, Graduate School of Biostudies, Kyoto University, Kyoto, Japan .
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Katsukawa
authors.affiliation: 1 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan .
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: 1 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan .
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukumoto
authors.affiliation: 1 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan .
authors.forename: Daisuke
authors.initials: D
authors.lastname: Doi
authors.affiliation: 1 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University , Kyoto, Japan .|3 Department of Neurosurgery, Clinical Neuroscience, Kyoto University Graduate School of Medicine , Kyoto, Japan .
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
mesh_terms: D063646:Carcinogenesis / Q000473:pathology* / Q000528:radiation effects*; D002454:Cell Differentiation / Q000528:radiation effects; D002460:Cell Line; D049109:Cell Proliferation / Q000528:radiation effects; D059290:Dopaminergic Neurons / Q000166:cytology / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000528:radiation effects; D008636:Mesencephalon / Q000166:cytology; D058953:Neural Stem Cells / Q000473:pathology* / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000166:cytology / Q000528:radiation effects; D033581:Stem Cell Transplantation