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.
Highlights
Since the development of human-induced pluripotent stem cells (Takahashi et al, 2007; Yu et al, 2007), various types of hiPSC-derived cells have been established that can beHow to cite this article Fukusumi et al (2018), Small-scale screening of anticancer drugs acting on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test
Another strategy is to use drugs to suppress the in vivo overgrowth of transplanted cells; for instance, pretreating hiPSC-Neural stem/progenitor cells (NSPCs) with a γ-secretase inhibitor inhibits Notch signaling, which is required for maintaining NSPC stemness (Okubo et al, 2016)
Cisplatin and etoposide were preferentially toxic to hN-NSPCs and hiPSC-NSPCs, respectively
Summary
Since the development of human-induced pluripotent stem cells (hiPSCs) (Takahashi et al, 2007; Yu et al, 2007), various types of hiPSC-derived cells have been established that can beHow to cite this article Fukusumi et al (2018), Small-scale screening of anticancer drugs acting on neural stem/progenitor cells derived from human-induced pluripotent stem cells using a time-course cytotoxicity test. The intrinsic proliferative potential of hiPSC-NSPCs, which makes them promising sources for large numbers of cells in vitro, can be a double-edged sword in vivo: transplanted cells can proliferate excessively before terminal differentiation in specific microenvironments Such undesired proliferation has not generally produced teratomas, malignant carcinogenesis, or other serious adverse events (Nori et al, 2015; Sugai et al, 2016), this inherent potential suggests the need for backup safety measures for stem cell–based therapies. Inserting exogenous genes into the donor-cell genome contradicts the purpose of integration-free hiPSCs, which are generated to minimize the risk of genetic modification or transgene re-activation, and transgenic strategies may create new risks despite the use of ‘genomic safe harbors’ for insertions in the human genome Another strategy is to use drugs to suppress the in vivo overgrowth of transplanted cells; for instance, pretreating hiPSC-NSPCs with a γ-secretase inhibitor inhibits Notch signaling, which is required for maintaining NSPC stemness (Okubo et al, 2016). A useful backup safety measure would be a method to chemically ablate transplanted cells, preferably with a cytotoxic drug that acts on transplanted hiPSC-NSPCs but not tissue-resident NSPCs
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