Direct reprogramming of mouse fibroblasts to neural progenitors

Proc Natl Acad Sci U S A. 2011 May 10;108(19):7838-43. doi: 10.1073/pnas.1103113108. Epub 2011 Apr 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Lineage
  • Cell Proliferation
  • Cell Transdifferentiation*
  • Culture Media
  • Cytological Techniques
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism*
  • Gene Expression
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / biosynthesis
  • Mice
  • Models, Biological
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism*
  • Octamer Transcription Factor-3 / biosynthesis
  • Octamer Transcription Factor-3 / genetics
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • SOXB1 Transcription Factors / biosynthesis
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism

Substances

  • Culture Media
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SOXB1 Transcription Factors
  • Sox1 protein, mouse
  • Sox2 protein, mouse