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PeerJ. 2018 Jan 4;6:e4187. doi: 10.7717/peerj.4187. eCollection 2018.

Small-scale screening of anticancer drugs acting specifically on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test.

Author information

1
Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
2
Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
3
Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
4
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

Abstract

Since the development of human-induced pluripotent stem cells (hiPSCs), various types of hiPSC-derived cells have been established for regenerative medicine and drug development. Neural stem/progenitor cells (NSPCs) derived from hiPSCs (hiPSC-NSPCs) have shown benefits for regenerative therapy of the central nervous system. However, owing to their intrinsic proliferative potential, therapies using transplanted hiPSC-NSPCs carry an inherent risk of undesired growth in vivo. Therefore, it is important to find cytotoxic drugs that can specifically target overproliferative transplanted hiPSC-NSPCs without damaging the intrinsic in vivo stem-cell system. Here, we examined the chemosensitivity of hiPSC-NSPCs and human neural tissue-derived NSPCs (hN-NSPCs) to the general anticancer drugs cisplatin, etoposide, mercaptopurine, and methotrexate. A time-course analysis of neurospheres in a microsphere array identified cisplatin and etoposide as fast-acting drugs, and mercaptopurine and methotrexate as slow-acting drugs. Notably, the slow-acting drugs were eventually cytotoxic to hiPSC-NSPCs but not to hN-NSPCs, a phenomenon not evident in the conventional endpoint assay on day 2 of treatment. Our results indicate that slow-acting drugs can distinguish hiPSC-NSPCs from hN-NSPCs and may provide an effective backup safety measure in stem-cell transplant therapies.

KEYWORDS:

ATP assay; Anticancer drugs; Drug screening; Endpoint assay; Human fetal neural tissue; Human-induced pluripotent stem cells; Microsphere array; Neural stem/progenitor cells; Neurosphere; Time-course cytotoxicity test

Conflict of interest statement

The authors declare there are no competing interests.

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