{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:12:34Z","timestamp":1791508354228,"version":"4.3.4"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T00:00:00Z","timestamp":1567555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009330","name":"Medical Science and Technology Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"DOI":"10.3389\/fnins.2019.00867","type":"journal-article","created":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T12:42:36Z","timestamp":1567600956000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Valproic Acid Enhances Reprogramming Efficiency and Neuronal Differentiation on Small Molecules Staged-Induction Neural Stem Cells: Suggested Role of mTOR Signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Qingrui","family":"Duan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Sunnassee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1002\/stem.408","article-title":"Inhibition of notch signaling in human embryonic stem cell-derived neural stem cells delays G1\/S phase transition and accelerates neuronal differentiation in vitro and in vivo.","volume":"28","author":"Borghese","year":"2010","journal-title":"Stem Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","article-title":"Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling.","volume":"27","author":"Chambers","year":"2009","journal-title":"Nat. Biotechnol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/cr.2014.32","article-title":"Generation of neural progenitor cells by chemical cocktails and hypoxia.","volume":"24","author":"Cheng","year":"2014","journal-title":"Cell Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/nrn1665","article-title":"WNTs in the vertebrate nervous system: from patterning to neuronal connectivity.","volume":"6","author":"Ciani","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"5107","DOI":"10.1074\/jbc.M807745200","article-title":"Cdc42-mTOR signaling pathway controls Hes5 and Pax6 expression in retinoic acid-dependent neural differentiation.","volume":"284","author":"Endo","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1002\/jcb.22775","article-title":"Teratomas from pluripotent stem cells: a clinical hurdle.","volume":"111","author":"Fong","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/nrm1175","article-title":"Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis.","volume":"4","author":"Grunert","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"999","DOI":"10.2353\/ajpath.2009.080537","article-title":"Valproic acid activates the PI3K\/Akt\/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy.","volume":"174","author":"Gurpur","year":"2009","journal-title":"Am. J. Pathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.stem.2012.02.021","article-title":"Direct reprogramming of fibroblasts into neural stem cells by defined factors.","volume":"10","author":"Han","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/4304916","article-title":"Direct reprogramming of mouse fibroblasts to neural stem cells by small molecules.","volume":"2016","author":"Han","year":"2016","journal-title":"Stem Cells Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1111\/j.1365-2796.2009.02155.x","article-title":"Neuronal cell replacement in Parkinson\u2019s disease.","volume":"266","author":"Hedlund","year":"2009","journal-title":"J. Intern. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"16659","DOI":"10.1073\/pnas.0407643101","article-title":"Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells.","volume":"101","author":"Hsieh","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/nbt1418","article-title":"Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds.","volume":"26","author":"Huangfu","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.stem.2009.09.012","article-title":"A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog.","volume":"5","author":"Ichida","year":"2009","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/849186","article-title":"mTOR inhibition: from aging to autism and beyond.","volume":"2013","author":"Kaeberlein","year":"2013","journal-title":"Scientifica"},{"key":"B16","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1111\/j.1471-4159.2004.02725.x","article-title":"The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells.","volume":"91","author":"Laeng","year":"2004","journal-title":"J. Neurochem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.celrep.2015.04.056","article-title":"Single transcription factor conversion of human blood fate to NPCs with CNS and PNS developmental capacity.","volume":"11","author":"Lee","year":"2015","journal-title":"Cell Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.stem.2010.04.014","article-title":"A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts.","volume":"7","author":"Li","year":"2010","journal-title":"Cell Stem Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1089\/scd.2017.0282","article-title":"Small molecules for neural stem cell induction.","volume":"27","author":"Liu","year":"2018","journal-title":"Stem Cells Dev."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0135479","article-title":"Induction of neural progenitor-like cells from human fibroblasts via a genetic material-free approach.","volume":"10","author":"Mirakhori","year":"2015","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/cr.2011.107","article-title":"Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1.","volume":"21","author":"Moon","year":"2011","journal-title":"Cell Res."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-10394-y","article-title":"Small molecule-based lineage switch of human adipose-derived stem cells into neural stem cells and functional GABAergic neurons.","volume":"7","author":"Park","year":"2017","journal-title":"Sci. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"36734","DOI":"10.1074\/jbc.M101287200","article-title":"Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.","volume":"276","author":"Phiel","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.mcn.2016.06.004","article-title":"Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.","volume":"75","author":"Qin","year":"2016","journal-title":"Mol. Cell. Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.stem.2012.05.018","article-title":"Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor.","volume":"11","author":"Ring","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.ydbio.2007.10.003","article-title":"Inhibition of Activin\/Nodal signaling promotes specification of human embryonic stem cells into neuroectoderm.","volume":"313","author":"Smith","year":"2008","journal-title":"Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors.","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.mce.2013.12.008","article-title":"Valproic acid enhances Oct4 promoter activity through PI3K\/Akt\/mTOR pathway activated nuclear receptors.","volume":"383","author":"Teng","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.stem.2012.03.003","article-title":"Direct conversion of fibroblasts into stably expandable neural stem cells.","volume":"10","author":"Thier","year":"2012","journal-title":"Cell Stem Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/ncb0901-778","article-title":"Isolation of multipotent adult stem cells from the dermis of mammalian skin.","volume":"3","author":"Toma","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1091\/mbc.e04-08-0658","article-title":"TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition.","volume":"16","author":"Valcourt","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1007\/s12035-014-8751-4","article-title":"Valproic acid alleviates memory deficits and attenuates amyloid-beta deposition in transgenic mouse model of Alzheimer\u2019s disease.","volume":"51","author":"Xuan","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.neuropharm.2008.09.019","article-title":"Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation.","volume":"56","author":"Yu","year":"2009","journal-title":"Neuropharmacology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.stem.2015.09.012","article-title":"Small molecules efficiently reprogram human astroglial cells into functional neurons.","volume":"17","author":"Zhang","year":"2015","journal-title":"Cell Stem Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.stem.2016.03.020","article-title":"Pharmacological reprogramming of fibroblasts into neural stem cells by signaling-directed transcriptional activation.","volume":"18","author":"Zhang","year":"2016","journal-title":"Cell Stem Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1016\/j.stemcr.2017.04.006","article-title":"PI3K\/AKT\/mTOR signaling mediates valproic acid-induced neuronal differentiation of neural stem cells through epigenetic modifications.","volume":"8","author":"Zhang","year":"2017","journal-title":"Stem Cell Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.bbrc.2016.05.080","article-title":"A combination of small molecules directly reprograms mouse fibroblasts into neural stem cells.","volume":"476","author":"Zheng","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fnins.2019.00867\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,2]],"date-time":"2019-10-02T02:40:10Z","timestamp":1569984010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fnins.2019.00867\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,4]]},"references-count":38,"alternative-id":["10.3389\/fnins.2019.00867"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2019.00867","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,4]]},"article-number":"867"}}