Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors

• DOI: 10.1016/j.stem.2012.02.021
• Publication Date: 2012-03-22T17:45:45Z
• Authors: Dong Wook Han; Natalia Tapia; Andreas Hermann; Kathrin Hemmer; Susanne Höing; Marcos J. Araúzo-...; Holm Zaehres; Guangming Wu; Stefan Frank; Sören Moritz; Boris Greber; Ji Hun Yang; Hoon Taek Lee; Jens C. Schwamborn; Alexander Storch; Hans R. Schöler
• Keywords: Reprogramming

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 identity-which 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.