Janghwan Kim^a,b, Jem A. Efe^a, Saiyong Zhu^a, Maria Talantova^c, Xu Yuan^a, Shufen Wang^d,e, Stuart A. Lipton^c, Kang Zhang^d,e, and Sheng Ding^a,f,1

^aDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
^bDevelopment and Differentiation Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, 305-806, Republic of Korea;
^cDel E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
^dInstitute for Genomic Medicine and Shiley Eye Center, University of California at San Diego, La Jolla, CA 92093;
^eMolecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610065, China; and
^fGladstone Institute of Cardiovascular Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158

Edited* by Clifford J. Tabin, Harvard Medical School, Boston, MA, and approved March 29, 2011 (received for review February 24, 2011)

Abstract
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 lineage-specific 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-factor–based reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation.

Footnotes
¹To whom correspondence should be addressed.

Author contributions: J.K., K.Z., and S.D. designed research; J.K., J.A.E., S.Z., M.T., X.Y., S.W., and S.A.L. performed research; J.K., J.A.E., S.Z., M.T., X.Y., S.A.L., and S.D. analyzed data; and J.K., K.Z., and S.D. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1103113108/-/DCSupplemental.