Abstract 15567: Glutamine Regulates Cardiac Stem Cell Metabolism and Competency
Objective: Cardiac stem cells (CSCs) increase myocardial function in the damaged heart; however, the mechanisms that contribute to their reparative qualities remain poorly understood. Because intermediary metabolism likely integrates characteristics involved in CSC competency, we examined CSC metabolism in the undifferentiated and early differentiated cell states.
Methods and Results: CSCs (c-kit+/lin-) isolated from mouse heart were positive for mesenchymal stem cell antigens (e.g., CD24/CD29/CD90.2/CD105) and relatively devoid of markers of differentiated cardiovascular cells. Early differentiation of CSCs increased the expression of smooth muscle, endothelial, and/or cardiomyocyte markers up to 60-fold, and increased expression of paracrine factors such as adiponectin (p<0.05). Differentiation was accompanied by increased abundance of mitochondrial electron transport chain subunits and a 33±5% and 42±3% increase in Complex I- and II-mediated respiration (p<0.05), respectively. Exposure to differentiation medium increased ASCT2 glutamine transporter abundance (up to 6-fold; p<0.0001) and decreased GAPDH (p<0.05). Glutamine increased mitochondrial oxygen consumption by up to 4.3-fold compared with provision of glucose, pyruvate or BSA-palmitate alone (p<0.05). Glutamine also stimulated fatty acid oxidation capacity by 32±10% (p<0.05). As expected in highly proliferative cells, [U-13C,15N]-Gln isotopologue analysis showed rapid incorporation of 13C and 15N into nucleotides; 13C was also found in the acyl chains of phospholipids and triacylglycerols. The doubling time of undifferentiated CSCs was increased by glutamine in a concentration-dependent manner (p<0.0001), and glutamine increased phosphorylation of p70S6k, indicating its capacity to activate mTOR and function as a growth factor.
Conclusions: CSCs have mesenchymal stem cell characteristics and rely primarily upon glutamine to meet metabolic demands. Differentiation increases the expression of not only markers of cardiovascular cells, but also that of paracrine factors and the glutamine transporter. Interventions that increase glutamine uptake may improve CSC therapeutic efficacy by enhancing CSC metabolism and proliferation.
- Energy metabolism
- Cardiovascular disease
- Stem cell therapy
- Mitochondrial energetics, heart failure, arrhythmias
- Heart failure
Author Disclosures: J.K. Salabei: None. P.K. Lorkiewicz: None. C.R. Holden: None. M.A. Harbeson: None. Q. Li: None. R. Bolli: None. A. Bhatnagar: None. B.G. Hill: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.