Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation

Joshua K. Salabei, Pawel K. Lorkiewicz, Candice R. Holden, Qianhong Li, Kyung U. Hong, Roberto Bolli, Aruni Bhatnagar, Bradford G. Hill

Research output: Contribution to journalArticle

Abstract

Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td=13.8 hours). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose (Glc) concentration, in the absence of insulin. Although high Glc concentrations did not stimulate proliferation, glutamine (Gln) increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with Glc, pyruvate (Pyr) or BSA-palmitate, Gln, when provided as the sole metabolic substrate, increased ATP-linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, Gln-induced respiration was doubled in the presence of BSA-palmitate, suggesting that Gln stimulates fatty acid oxidation. Additionally, Gln promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable α-ketoglutarate in the absence of Gln increased both respiration and cell proliferation, indicating a key role of Gln anaplerosis in cell growth. These findings suggest that Gln, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase Gln uptake or oxidation may improve CPC therapy. Stem Cells 2015;33:2613 - 2627

Original languageEnglish (US)
Pages (from-to)2613-2627
Number of pages15
JournalStem Cells
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

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Glutamine
Stem Cells
Cell Proliferation
Respiration
Palmitates
Glucose
Fatty Acids
70-kDa Ribosomal Protein S6 Kinases
Retinoblastoma Protein
Autologous Transplantation
Cyclin D1
Growth
Cell- and Tissue-Based Therapy
Metabolic Networks and Pathways
Pyruvic Acid
Oxidative Stress
Carbon
Adenosine Triphosphate
Phosphorylation
Insulin

Keywords

  • Bioenergetics
  • Cell therapy
  • Heart failure
  • Mitochondria
  • Proliferation
  • Stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Salabei, J. K., Lorkiewicz, P. K., Holden, C. R., Li, Q., Hong, K. U., Bolli, R., ... Hill, B. G. (2015). Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. Stem Cells, 33(8), 2613-2627. https://doi.org/10.1002/stem.2047

Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. / Salabei, Joshua K.; Lorkiewicz, Pawel K.; Holden, Candice R.; Li, Qianhong; Hong, Kyung U.; Bolli, Roberto; Bhatnagar, Aruni; Hill, Bradford G.

In: Stem Cells, Vol. 33, No. 8, 01.08.2015, p. 2613-2627.

Research output: Contribution to journalArticle

Salabei, JK, Lorkiewicz, PK, Holden, CR, Li, Q, Hong, KU, Bolli, R, Bhatnagar, A & Hill, BG 2015, 'Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation', Stem Cells, vol. 33, no. 8, pp. 2613-2627. https://doi.org/10.1002/stem.2047
Salabei JK, Lorkiewicz PK, Holden CR, Li Q, Hong KU, Bolli R et al. Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. Stem Cells. 2015 Aug 1;33(8):2613-2627. https://doi.org/10.1002/stem.2047
Salabei, Joshua K. ; Lorkiewicz, Pawel K. ; Holden, Candice R. ; Li, Qianhong ; Hong, Kyung U. ; Bolli, Roberto ; Bhatnagar, Aruni ; Hill, Bradford G. / Glutamine Regulates Cardiac Progenitor Cell Metabolism and Proliferation. In: Stem Cells. 2015 ; Vol. 33, No. 8. pp. 2613-2627.
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abstract = "Autologous transplantation of cardiac progenitor cells (CPCs) alleviates myocardial dysfunction in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. In this study, we examined CPC metabolism to elucidate the metabolic pathways that regulate their proliferative capacity. In complete growth medium, undifferentiated CPCs isolated from adult mouse heart proliferated rapidly (Td=13.8 hours). CPCs expressed the Glut1 transporter and their glycolytic rate was increased by high extracellular glucose (Glc) concentration, in the absence of insulin. Although high Glc concentrations did not stimulate proliferation, glutamine (Gln) increased CPC doubling time and promoted survival under conditions of oxidative stress. In comparison with Glc, pyruvate (Pyr) or BSA-palmitate, Gln, when provided as the sole metabolic substrate, increased ATP-linked and uncoupled respiration. Although fatty acids were not used as respiratory substrates when present as a sole carbon source, Gln-induced respiration was doubled in the presence of BSA-palmitate, suggesting that Gln stimulates fatty acid oxidation. Additionally, Gln promoted rapid phosphorylation of the mTORC1 substrate, p70S6k, as well as retinoblastoma protein, followed by induction of cyclin D1 and cdk4. Inhibition of either mTORC1 or glutaminolysis was sufficient to diminish CPC proliferation, and provision of cell permeable α-ketoglutarate in the absence of Gln increased both respiration and cell proliferation, indicating a key role of Gln anaplerosis in cell growth. These findings suggest that Gln, by enhancing mitochondrial function and stimulating mTORC1, increases CPC proliferation, and that interventions to increase Gln uptake or oxidation may improve CPC therapy. Stem Cells 2015;33:2613 - 2627",
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