ERRs Mediate a Metabolic Switch Required for Somatic Cell Reprogramming to Pluripotency

Cell Stem Cell. 2015 May 7;16(5):547-55. doi: 10.1016/j.stem.2015.03.001. Epub 2015 Apr 9.

Abstract

Cell metabolism is adaptive to extrinsic demands; however, the intrinsic metabolic demands that drive the induced pluripotent stem cell (iPSC) program remain unclear. Although glycolysis increases throughout the reprogramming process, we show that the estrogen-related nuclear receptors (ERRα and ERRγ) and their partnered co-factors PGC-1α and PGC-1β are transiently induced at an early stage, resulting in a burst of oxidative phosphorylation (OXPHOS) activity. Upregulation of ERRα or ERRγ is required for the OXPHOS burst in both human and mouse cells, respectively, as well as iPSC generation itself. Failure to induce this metabolic switch collapses the reprogramming process. Furthermore, we identify a rare pool of Sca1(-)/CD34(-) sortable cells that is highly enriched in bona fide reprogramming progenitors. Transcriptional profiling confirmed that these progenitors are ERRγ and PGC-1β positive and have undergone extensive metabolic reprogramming. These studies characterize a previously unrecognized, ERR-dependent metabolic gate prior to establishment of induced pluripotency.

Publication types

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

MeSH terms

  • Adult Stem Cells / physiology*
  • Animals
  • Antigens, CD34 / metabolism
  • Ataxin-1 / metabolism
  • Cell Line
  • Cellular Reprogramming
  • Humans
  • Mice
  • Mice, Knockout
  • Oxidative Phosphorylation
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Pluripotent Stem Cells / physiology*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Transcription Factors / metabolism

Substances

  • Antigens, CD34
  • Ataxin-1
  • ERRalpha estrogen-related receptor
  • Esrrg protein, mouse
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Receptors, Estrogen
  • Transcription Factors

Associated data

  • GEO/GSE31704