Dong Wook Han^1,2,7, Natalia Tapia^1,7, Andreas Hermann^3,4, Kathrin Hemmer⁵, Susanne Hoing¹, Marcos J. Arauzo-Bravo¹, Holm Zaehres¹, Guangming Wu¹, Stefan Frank¹, Soren Moritz¹, Boris Greber¹, Ji Hun Yang¹, Hoon Taek Lee², Jens C. Schwamborn⁵, Alexander Storch^3,4, Hans R. Scholer^1,6

¹ Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Rontgenstrasse 20, 48149 Munster, Germany
² Department of Stem Cell Biology, School of Medicine, SMART Institute of Advanced Biomedical Science, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea
³ Division of Neurodegenerative Diseases, Department of Neurology and Center for Regenerative Therapies Dresden (CRTD), Dresden University of Technology, 01307 Dresden, Germany
⁴ German Centre for Neurodegenerative Diseases (DZNE), 01307 Dresden, Germany
⁵ Westfalische Wilhelms-Universitat Munster, ZMBE, Institute of Cell Biology, Stem Cell Biology and Regeneration Group, Von-Esmarch-Str. 56, 48149 Munster, Germany
⁶ Medical Faculty, University of Munster, Domagkstrasse 3, 48149 Munster, Germany
⁷These authors contributed equally to this work

Corresponding author : Dong Wook Han
Corresponding author : Hans R. Scholer

Summary
Recent studies have shown that defined sets of transcription factors can directly reprogram differentiated somatic cells to a different differentiated cell type without passing through a pluripotent state, but the restricted proliferative and lineage potential of the resulting cells limits the scope of their potential applications. Here we show that a combination of transcription factors (Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3) induces mouse fibroblasts to directly acquire a neural stem cell identitywhich we term as induced neural stem cells (iNSCs). Direct reprogramming of fibroblasts into iNSCs is a gradual process in which the donor transcriptional program is silenced over time. iNSCs exhibit cell morphology, gene expression, epigenetic features, differentiation potential, and self-renewing capacity, as well as in vitro and in vivo functionality similar to those of wild-type NSCs. We conclude that differentiated cells can be reprogrammed directly into specific somatic stem cell types by defined sets of specific transcription factors.