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

Ayesha Zafir, Ryan Readnower, Bethany W. Long, James McCracken, Allison Aird, Alejandro Alvarez, Timothy D. Cummins, Qianhong Li, Bradford G. Hill, Aruni Bhatnagar, Sumanth D. Prabhu, Roberto Bolli, Steven P. Jones

Research output: Contribution to journalArticle

Abstract

Clinical trials demonstrate the regenerative potential of cardiac stem cell (CSC) therapy in the postinfarcted heart. Despite these encouraging preliminary clinical findings, the basic biology of these cells remains largely unexplored. The principal requirement for cell transplantation is to effectively prime them for survival within the unfavorable environment of the infarcted myocardium. In the adult mammalian heart, the β-O-linkage of N-acetylglucosamine (i.e., O-GlcNAc) to proteins is a unique post-translational modification that confers cardioprotection from various otherwise lethal stressors. It is not known whether this signaling system exists in CSCs. In this study, we demonstrate that protein O-GlcNAcylation is an inducible stress response in adult murine Sca-1+/lin- CSCs and exerts an essential prosurvival role. Posthypoxic CSCs responded by time-dependently increasing protein O-GlcNAcylation upon reoxygenation. We used pharmacological interventions for loss- and gain-of-function, that is, enzymatic inhibition of O-GlcNAc transferase (OGT) (adds the O-GlcNAc modification to proteins) by TT04, or inhibition of OGA (removes O-GlcNAc) by thiamet-G (ThG). Reduction in the O-GlcNAc signal (via TT04, or OGT gene deletion using Cre-mediated recombination) significantly sensitized CSCs to posthypoxic injury, whereas augmenting O-GlcNAc levels (via ThG) enhanced cell survival. Diminished O-GlcNAc levels render CSCs more susceptible to the onset of posthypoxic apoptotic processes via elevated poly(ADP-ribose) polymerase cleavage due to enhanced caspase-3/7 activation, whereas promoting OGlcNAcylation can serve as a pre-emptive antiapoptotic signal regulating the survival of CSCs. Thus, we report the primary demonstration of protein O-GlcNAcylation as an important prosurvival signal in CSCs, which could enhance CSC survival prior to in vivo autologous transfer.

Original languageEnglish (US)
Pages (from-to)765-775
Number of pages11
JournalStem Cells
Volume31
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Fingerprint

Stem Cells
Proteins
Cell Survival
Caspase 7
Gastrin-Secreting Cells
Acetylglucosamine
Poly(ADP-ribose) Polymerases
Cell Transplantation
Gene Deletion
Post Translational Protein Processing
Cell- and Tissue-Based Therapy
Caspase 3
Genetic Recombination
Cell Biology
Myocardium
Clinical Trials
Pharmacology
Wounds and Injuries
O-GlcNAc transferase
thiamet G

Keywords

  • Adult stem cells
  • Cardiac
  • Cell biology
  • Hypoxia
  • Tissue-specific stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Zafir, A., Readnower, R., Long, B. W., McCracken, J., Aird, A., Alvarez, A., ... Jones, S. P. (2013). Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells. Stem Cells, 31(4), 765-775. https://doi.org/10.1002/stem.1325

Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells. / Zafir, Ayesha; Readnower, Ryan; Long, Bethany W.; McCracken, James; Aird, Allison; Alvarez, Alejandro; Cummins, Timothy D.; Li, Qianhong; Hill, Bradford G.; Bhatnagar, Aruni; Prabhu, Sumanth D.; Bolli, Roberto; Jones, Steven P.

In: Stem Cells, Vol. 31, No. 4, 04.2013, p. 765-775.

Research output: Contribution to journalArticle

Zafir, A, Readnower, R, Long, BW, McCracken, J, Aird, A, Alvarez, A, Cummins, TD, Li, Q, Hill, BG, Bhatnagar, A, Prabhu, SD, Bolli, R & Jones, SP 2013, 'Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells', Stem Cells, vol. 31, no. 4, pp. 765-775. https://doi.org/10.1002/stem.1325
Zafir A, Readnower R, Long BW, McCracken J, Aird A, Alvarez A et al. Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells. Stem Cells. 2013 Apr;31(4):765-775. https://doi.org/10.1002/stem.1325
Zafir, Ayesha ; Readnower, Ryan ; Long, Bethany W. ; McCracken, James ; Aird, Allison ; Alvarez, Alejandro ; Cummins, Timothy D. ; Li, Qianhong ; Hill, Bradford G. ; Bhatnagar, Aruni ; Prabhu, Sumanth D. ; Bolli, Roberto ; Jones, Steven P. / Protein O-GlcNAcylation is a novel cytoprotective signal in cardiac stem cells. In: Stem Cells. 2013 ; Vol. 31, No. 4. pp. 765-775.
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