title: Direct conversion of fibroblasts into stably expandable neural stem cells.
abstract: Recent advances have suggested that direct induction of neural stem cells (NSCs) could provide an alternative to derivation from somatic tissues or pluripotent cells. Here we show direct derivation of stably expandable NSCs from mouse fibroblasts through a curtailed version of reprogramming to pluripotency. By constitutively inducing Sox2, Klf4, and c-Myc while strictly limiting Oct4 activity to the initial phase of reprogramming, we generated neurosphere-like colonies that could be expanded for more than 50 passages and do not depend on sustained expression of the reprogramming factors. These induced neural stem cells (iNSCs) uniformly display morphological and molecular features of NSCs, such as the expression of Nestin, Pax6, and Olig2, and have a genome-wide transcriptional profile similar to that of brain-derived NSCs. Moreover, iNSCs can differentiate into neurons, astrocytes, and oligodendrocytes. Our results demonstrate that functional NSCs can be generated from somatic cells by factor-driven induction.
authors.affiliation: Stem Cell Engineering Group at the Institute of Reconstructive Neurobiology, University of Bonn, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Thier
authors.forename: Philipp
authors.initials: P
authors.lastname: Wörsdörfer
authors.forename: Yenal B
authors.initials: YB
authors.lastname: Lakes
authors.forename: Raphaela
authors.initials: R
authors.lastname: Gorris
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.forename: Thoralf
authors.initials: T
authors.lastname: Opitz
authors.forename: Dominic
authors.initials: D
authors.lastname: Seiferling
authors.forename: Tamara
authors.initials: T
authors.lastname: Quandel
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.forename: Frank
authors.initials: F
authors.lastname: Edenhofer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D000090062:Kruppel-Like Factor 4; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000096:biosynthesis; D014183:Transplantation, Heterologous
chemical_list: C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors