Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain

Stem Cell Res. Sep-Nov 2009;3(2-3):142-56. doi: 10.1016/j.scr.2009.07.002. Epub 2009 Aug 3.

Abstract

Human embryonic stem cell (hESC) pluripotency has been reported by several groups to be best maintained by culture under physiological oxygen conditions. Building on that finding, we inhibited complex III of the mitochondrial respiratory chain using antimycin A or myxothiazol to examine if specifically targeting the mitochondria would have a similar beneficial result for the maintenance of pluripotency. hESCs grown in the presence of 20 nM antimycin A maintained a compact morphology with high nuclear/cytoplasmic ratios. Furthermore, real-time PCR analysis demonstrated that the levels of Nanog mRNA were elevated 2-fold in antimycin A-treated cells. Strikingly, antimycin A was also able to replace bFGF in the media without compromising pluripotency, as long as autocrine bFGF signaling was maintained. Further analysis using low-density quantitative PCR arrays showed that antimycin A treatment reduced the expression of genes associated with differentiation, possibly acting through a ROS-mediated pathway. These results demonstrate that modulation of mitochondrial function results in increased pluripotency of the cell population, and sheds new light on the mechanisms and signaling pathways modulating hESC pluripotency.

Publication types

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

MeSH terms

  • Antimycin A / pharmacology
  • Electron Transport Complex III / antagonists & inhibitors*
  • Electron Transport Complex III / metabolism
  • Embryonic Stem Cells / cytology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mitochondria / metabolism*
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Pluripotent Stem Cells / cytology*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction

Substances

  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • Reactive Oxygen Species
  • Antimycin A
  • Electron Transport Complex III