Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling

Cell Cycle. 2014;13(22):3576-89. doi: 10.4161/15384101.2014.962951.

Abstract

The low survival and differentiation rates of stem cells after either transplantation or neural injury have been a major concern of stem cell-based therapy. Thus, further understanding long-term survival and differentiation of stem cells may uncover new targets for discovery and development of novel therapeutic approaches. We have previously described the impact of mitochondrial apoptosis-related events in modulating neural stem cell (NSC) fate. In addition, the endogenous bile acid, tauroursodeoxycholic acid (TUDCA) was shown to be neuroprotective in several animal models of neurodegenerative disorders by acting as an anti-apoptotic and anti-oxidant molecule at the mitochondrial level. Here, we hypothesize that TUDCA might also play a role on NSC fate decision. We found that TUDCA prevents mitochondrial apoptotic events typical of early-stage mouse NSC differentiation, preserves mitochondrial integrity and function, while enhancing self-renewal potential and accelerating cell cycle exit of NSCs. Interestingly, TUDCA prevention of mitochondrial alterations interfered with NSC differentiation potential by favoring neuronal rather than astroglial conversion. Finally, inhibition of mitochondrial reactive oxygen species (mtROS) scavenger and adenosine triphosphate (ATP) synthase revealed that the effect of TUDCA is dependent on mtROS and ATP regulation levels. Collectively, these data underline the importance of mitochondrial stress control of NSC fate decision and support a new role for TUDCA in this process.

Keywords: ATP; ATP, adenosine triphosphate; BrdU, bromodeoxyuridine; CsA, cyclosporin A; DiOC6(3), 3, 3′-dihexyloxacarbocyanine iodide; FACS, fluorescence-activated cell sorting analysis; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; MnSOD, manganese superoxide dismutase; NSC, neural stem cells; OGG1, 8-oxoguanine DNA glycosylase; OligA, oligomycin A; ROS, reactive oxygen species; Sox2, sex determining region Y- box 2; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; VDAC, voltage-dependent anion channel; cdk, cyclin-dependent kinase; cell cycle; mitochondrial oxidative stress; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; neural stem cell fate; tauroursodeoxycholic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Astrocytes / drug effects
  • Cell Communication / drug effects
  • Cell Cycle / drug effects*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Taurochenodeoxycholic Acid / administration & dosage

Substances

  • Reactive Oxygen Species
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine