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
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
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DOI：
10.7717/peerj.4187
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发表时间：
2018-01-04
期刊：
影响因子：
2.7
通讯作者：
Kanemura, Yonehiro
中科院分区：
文献类型：
--
作者：
Fukusumi, Hayato;Handa, Yukako;Kanemura, Yonehiro
自从人类诱导的多能干细胞（hiPSC）的开发以来，已经建立了用于再生医学和药物开发的各种类型的hiPSC衍生的细胞。来源于hiPSC的神经干/祖细胞（NSPCs）（hiPSC-NSPCs）已经显示出对中枢神经系统的再生治疗的益处。然而，由于其固有的增殖潜力，使用移植的hiPSC-NSPC的疗法具有体内不期望的生长的固有风险。因此，重要的是找到可以特异性靶向过度增殖的移植的hiPSC-NSPCs而不损害内在的体内干细胞系统的细胞毒性药物。在这里，我们研究了hiPSC-NSPCs和人神经组织来源的NSPCs（hN-NSPCs）对一般抗癌药物顺铂，依托泊苷，巯基嘌呤和甲氨蝶呤的化学敏感性。对微球阵列中的神经球进行时程分析，确定顺铂和依托泊苷为快速作用药物，巯基嘌呤和甲氨蝶呤为缓慢作用药物。值得注意的是，缓慢作用药物最终对hiPSC-NSPC具有细胞毒性，但对hN-NSPC没有细胞毒性，这是在治疗第2天的常规终点测定中不明显的现象。我们的研究结果表明，慢作用药物可以区分hiPSC-NSPCs和hN-NSPCs，并可能在干细胞移植治疗中提供有效的备用安全措施。
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.