Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors

Stem Cells. 2011 Jun;29(6):992-1000. doi: 10.1002/stem.641.

Abstract

Pluripotent cells can be derived from different types of somatic cells by nuclear reprogramming through the ectopic expression of four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc. However, it is unclear whether postmitotic neurons are susceptible to direct reprogramming. Here, we show that postnatal cortical neurons, the vast majority of which are postmitotic, are amenable to epigenetic reprogramming. However, ectopic expression of the four canonical reprogramming factors is not sufficient to reprogram postnatal neurons. Efficient reprogramming was only achieved after forced cell proliferation by p53 suppression. Additionally, overexpression of repressor element-1 silencing transcription, a suppressor of neuronal gene activity, increased reprogramming efficiencies in combination with the reprogramming factors. Our findings indicate that terminally differentiated postnatal neurons are able to acquire the pluripotent state by direct epigenetic reprogramming, and this process is made more efficient through the suppression of lineage specific gene expression.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Biomarkers / metabolism
  • Blastocyst / cytology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Embryo Transfer
  • Fibroblasts / cytology
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / metabolism
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation
  • Lewis X Antigen / metabolism
  • Mice
  • Nanog Homeobox Protein
  • Neurons / cytology*
  • Neurons / metabolism
  • Octamer Transcription Factor-3 / metabolism
  • Promoter Regions, Genetic
  • Repressor Proteins / metabolism*
  • Teratoma / pathology
  • Transplantation Chimera

Substances

  • Biomarkers
  • Homeodomain Proteins
  • Lewis X Antigen
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Green Fluorescent Proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2