Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance

Nat Commun. 2015 Jul 8;6:7398. doi: 10.1038/ncomms8398.

Abstract

The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Reprogramming / physiology*
  • Fibroblasts
  • Gene Expression Regulation / physiology
  • Humans
  • Mice
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology*
  • Netrin Receptors
  • Netrin-1
  • Pluripotent Stem Cells / physiology*
  • Promoter Regions, Genetic
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / pharmacology*

Substances

  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Netrin-1