title: Dormant Pluripotent Cells Emerge during Neural Differentiation of Embryonic Stem Cells in a FoxO3-Dependent Manner.
abstract: One major concern over the clinical application of embryonic stem cell (ESC)-derived cells is the potentiation of latent tumorigenicity by residual undifferentiated cells. Despite the use of intensive methodological approaches to eliminate residual undifferentiated cells, the properties of these cells remain elusive. Here, we show that under a serum-free neural differentiation condition, residual undifferentiated cells markedly delay progression of their cell cycle without compromising their pluripotency. This dormant pluripotency was maintained during reculture of the cells under a serum-free condition, whereas upon serum stimulation, the cells exited the dormant state and restarted proliferation and differentiation into all three germ layers. Microarray analysis revealed a set of genes that is significantly upregulated in the dormant ESCs compared with their levels of regulation in proliferating ESCs. Among them, we identified the transcription factor Forkhead box O3 (FoxO3) to be an essential regulator of the maintenance of pluripotency in dormant ESCs. Our study demonstrates that the transition into the dormant state endows residual undifferentiated cells with FoxO3-dependent and leukemia inhibitory factor/serum-independent pluripotency.
authors.affiliation: Department of Biosystems Science, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan.|Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Biosystems Science, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto, Japan ftoyoshi@virus.kyoto-u.ac.jp.|Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Toyoshima
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D015363:Quinolones
keywords: FoxO3; embryonic stem cells; pluripotency; regenerative medicine; stem cell quiescence