title: Reprogramming to pluripotency through a somatic stem cell intermediate.
abstract: Transcription factor-based reprogramming can lead to the successful switching of cell fates. We have recently reported that mouse embryonic fibroblasts (MEFs) can be directly reprogrammed into induced neural stem cells (iNSCs) after the forced expression of Brn4, Sox2, Klf4, and Myc. Here, we tested whether iNSCs could be further reprogrammed into induced pluripotent stem cells (iPSCs). The two factors Oct4 and Klf4 were sufficient to induce pluripotency in iNSCs. Immunocytochemistry and gene expression analysis showed that iNSC-derived iPSCs (iNdiPSCs) are similar to embryonic stem cells at the molecular level. In addition, iNdiPSCs could differentiate into cells of all three germ layers, both in vitro and in vivo, proving that iNdiPSCs are bona fide pluripotent cells. Furthermore, analysis of the global gene expression profile showed that iNdiPSCs, in contrast to iNSCs, do not retain any MEF transcriptional memory even at early passages after reprogramming. Overall, our results demonstrate that iNSCs can be reprogrammed to pluripotency and suggest that cell fate can be redirected numerous times. Importantly, our findings indicate that the induced pluripotent cell state may erase the donor-cell type epigenetic memory more efficiently than other induced somatic cell fates.
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Adele G
authors.initials: AG
authors.lastname: Marthaler
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Tiemann
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Guangming
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Holm
authors.initials: H
authors.lastname: Zaehres
authors.affiliation: Department of Nanobiomedical Science, Dankook University Graduate School, Cheonan, Republic of Korea ; Department of Rehabilitation Medicine, Dandook University, Cheonan, Republic of Korea.
authors.forename: Jung Keun
authors.initials: JK
authors.lastname: Hyun
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany ; Medical Faculty, University of Münster, Münster, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tapia
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D058953:Neural 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