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A microarray accession number was inadvertently omitted from this paper. Microarray data for this paper can be found at NCBI GEO (http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE16062.

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The simple yet powerful technique of induced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drug development. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requires reprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy this process can be, we sought to determine whether it might be possible to convert somatic cells into lineagespecific stem/progenitor cells of another germ layer in one step, bypassing the intermediate pluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells (NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directly converted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable in vitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results provide a unique paradigm for iPSC-factorbased reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation.A lthough successful transdifferentiation from one cell type to another by overexpressing lineage-specific genes in vivo (1, 2) and in vitro (3, 4) has been reported, until recently these methods were only effective for fate switching within the major lineages, i.e., ectoderm, mesoderm, and endoderm. However, the generation of iN cells (5) using neural-specific transcription factors has established that interlineage transdifferentiation is also possible in vitro. These transdifferentiation schemes entail overexpression of different sets of lineage-specific transcription factors. A more recent example reported single-factor transdifferentiation of fibroblasts into blood precursors using long-term ectopic expression of OCT4 (6); through extensive binding to the regulatory regions of key hematopoietic genes, OCT4 also appears to be participating in regulating hematopoietic programs acting as a lineage-specific transcription factor in this context. An important aspect of this study is the ability to generate a mitotically active progenitor population that can be further differentiated into a variety of blood cells-a critical feat that has yet to be accomplished in transdifferentiation to neural and endoderm lineages.In an effort to devise a more general transdifferentiation strategy that might give rise to a broad array of unrelated cell typesincluding lineage-specific precursors-we attempted to direct conventional four iPSC-factor-based reprogramming (7, 8) toward alternative outcomes. Specifically, studies indicating that iPSCs are generated in a sequential and stochastic manner (9-11) led us to hypothesize that we might be able to manipulate cells at an early and epigenetically highly unstable state induced by the reprogramming factors. Different conditions could potentially give rise to a multitude ...