Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion

Cell Stem Cell. 2008 Nov 6;3(5):493-507. doi: 10.1016/j.stem.2008.08.017.

Abstract

Reprogramming of nuclei allows the dedifferentiation of differentiated cells. Somatic cells can undergo epigenetic modifications and reprogramming through their fusion with embryonic stem cells (ESCs) or after overexpression of a specific blend of ESC transcription factor-encoding genes. We show here that cyclic activation of Wnt/beta-catenin signaling in ESCs with Wnt3a or the glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime (BIO) strikingly enhances the ability of ESCs to reprogram somatic cells after fusion. In addition, we show that reprogramming is triggered by a dose-dependent accumulation of active beta-catenin. Reprogrammed clones express ESC-specific genes, lose somatic differentiation markers, become demethylated on Oct4 and Nanog CpG islands, and can differentiate into cardiomyocytes in vitro and generate teratomas in vivo. Our data thus demonstrate that in ESCs, periodic beta-catenin accumulation via the Wnt/beta-catenin pathway provides a specific threshold that leads to the reprogramming of somatic cells after fusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Fusion
  • Cellular Reprogramming / physiology*
  • CpG Islands
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Homeodomain Proteins / metabolism
  • Hybrid Cells
  • Indoles / pharmacology
  • Mice
  • Mice, Transgenic
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3 / metabolism
  • Oximes / pharmacology
  • Signal Transduction / drug effects
  • Wnt Proteins / metabolism*
  • Wnt3 Protein
  • Wnt3A Protein
  • beta Catenin / metabolism*

Substances

  • 6-bromoindirubin-3'-oxime
  • Homeodomain Proteins
  • Indoles
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Oximes
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • Glycogen Synthase Kinase 3