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Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells

Ayesha Zafir1, Ryan Readnower, Bethany W Long

  • 1Department of Medicine, Division of Cardiovascular Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky 40202, USA.

Stem Cells (Dayton, Ohio)
|January 22, 2013
PubMed

Insights

Cardiac stem cell (CSC) therapy shows promise, but CSC survival needs improvement. This study reveals that protein O-GlcNAcylation is a key survival signal in CSCs, offering a new target to enhance cell therapy effectiveness.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research
  • Stem Cell Biology

Background:

  • Clinical trials highlight cardiac stem cell (CSC) therapy's regenerative potential for post-infarcted hearts.
  • The fundamental biology of CSCs, particularly their survival mechanisms in the harsh post-infarcted environment, remains underexplored.
  • Protein O-GlcNAcylation, a post-translational modification, is known to confer cardioprotection but its role in CSCs is unknown.

Purpose of the Study:

  • To investigate the presence and function of protein O-GlcNAcylation in adult murine Sca-1(+) /lin(-) cardiac stem cells (CSCs).
  • To determine if O-GlcNAcylation acts as a prosurvival mechanism in CSCs under stress conditions.
  • To explore the potential of modulating O-GlcNAcylation for enhancing CSC survival prior to transplantation.

Main Methods:

  • Adult murine Sca-1(+) /lin(-) CSCs were subjected to hypoxic stress followed by reoxygenation.
  • Pharmacological agents TT04 (OGT inhibitor) and thiamet-G (OGA inhibitor) were used for loss- and gain-of-function studies.
  • OGT gene deletion via Cre-mediated recombination was employed to further assess the role of O-GlcNAcylation.
  • Apoptosis markers, including caspase-3/7 activation and PARP cleavage, were analyzed.

Main Results:

  • Protein O-GlcNAcylation was found to be an inducible stress response in CSCs, increasing upon reoxygenation after hypoxia.
  • Inhibition of O-GlcNAcylation (using TT04 or OGT deletion) significantly increased CSC sensitivity to posthypoxic injury and apoptosis.
  • Augmentation of O-GlcNAcylation (using thiamet-G) enhanced CSC survival and acted as a pre-emptive antiapoptotic signal.

Conclusions:

  • Protein O-GlcNAcylation is a critical prosurvival signal in cardiac stem cells (CSCs).
  • Modulating O-GlcNAcylation levels can protect CSCs from apoptotic cell death induced by posthypoxic stress.
  • Targeting protein O-GlcNAcylation represents a promising strategy to improve CSC survival for enhanced efficacy in cardiac repair therapies.

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