title: Induction of Pluripotency in Astrocytes through a Neural Stem Cell-like State.
abstract: It remains controversial whether the routes from somatic cells to induced pluripotent stem cells (iPSCs) are related to the reverse order of normal developmental processes. Specifically, it remains unaddressed whether or not the differentiated cells become iPSCs through their original tissue stem cell-like state. Previous studies analyzing the reprogramming process mostly used fibroblasts; however, the stem cell characteristics of fibroblasts made it difficult to address this. Here, we generated iPSCs from mouse astrocytes, a type of glial cells, by three (OCT3/4, KLF4, and SOX2), two (OCT3/4 and KLF4), or four (OCT3/4, KLF4, and SOX2 plus c-MYC) factors. Sox1, a neural stem cell (NSC)-specific transcription factor, is transiently up-regulated during reprogramming, and Sox1-positive cells become iPSCs. The up-regulation of Sox1 is essential for OCT3/4- and KLF4-induced reprogramming. Genome-wide analysis revealed that the gene expression profile of Sox1-expressing intermediate-state cells resembles that of NSCs. Furthermore, the intermediate-state cells are able to generate neurospheres, which can differentiate into both neurons and glial cells. Remarkably, during fibroblast reprogramming, neither Sox1 up-regulation nor an increase in neurogenic potential occurs. Our results thus demonstrate that astrocytes are reprogrammed through an NSC-like state.
authors.affiliation: From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: May
authors.initials: M
authors.lastname: Nakajima-Koyama
authors.affiliation: From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502.
authors.forename: Joonseong
authors.initials: J
authors.lastname: Lee
authors.affiliation: From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, the Department of Reprogramming Science, Center for iPS Cell Research and Application, and.
authors.forename: Sho
authors.initials: S
authors.lastname: Ohta
authors.affiliation: CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan the Department of Reprogramming Science, Center for iPS Cell Research and Application, and Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8507, and.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan nishida@lif.kyoto-u.ac.jp.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D000067470:Cellular Reprogramming Techniques; D000090062:Kruppel-Like Factor 4; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors
keywords: astrocyte; development; induced pluripotent stem cell (iPS cell) (iPSC); neural stem cell (NSC); reprogramming