Curtis C Hughey1, Maria P Alfaro2, Darrell D Belke3, Jeffery N Rottman4, Pampee P Young5, David H Wasserman6, Jane Shearer7. 1. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, AB T2N 1N4 Canada ; University of Calgary, KNB Rm 3318. 2500 University Dr. NW, Calgary, Alberta Canada T2N 1N4. 2. Department of Pathology, School of Medicine, Vanderbilt University, Nashville, 37232 TN USA. 3. Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 1N4 Canada. 4. Department of Medicine, Division of Cardiovascular Medicine, School of Medicine, Vanderbilt University, Nashville, 37240 TN USA. 5. Department of Pathology, School of Medicine, Vanderbilt University, Nashville, 37232 TN USA ; Department of Veterans Affairs Medical Center, Nashville, 37232 TN USA. 6. Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, 37240 TN USA. 7. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, AB T2N 1N4 Canada ; Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 1N4 Canada.
Abstract
BACKGROUND: Cell-based therapies show promise in repairing cardiac tissue and improving contractile performance following a myocardial infarction. Despite this, ischemia-induced death of transplanted cells remains a major hurdle to the efficacy of treatment. 'Superhealer' MRL/MpJ mesenchymal stem cells (MRL-MSCs) have been reported to exhibit increased engraftment resulting in reduced infarct size and enhanced contractile function. This study determines whether intrinsic differences in mitochondrial oxidative phosphorylation (OXPHOS) assist in explaining the enhanced cellular survival and engraftment of MRL-MSCs. FINDINGS: Compared to wild type MSCs (WT-MSCs), mitochondria from intact MRL-MSCs exhibited an increase in routine respiration and maximal electron transport capacity by 2.0- and 3.5-fold, respectively. When routine oxygen utilization is expressed as a portion of maximal cellular oxygen flux, the MRL-MSCs have a greater spare respiratory capcity. Additionally, glutamate/malate succinate-supported oxygen consumption in permeabilized cells was elevated approximately 1.25- and 1.4-fold in the MRL-MSCs, respectively. CONCLUSION: The results from intact and permeabilized MSCs indicate MRL-MSCs exhibit a greater reliance on and capacity for aerobic metabolism. The greater capacity for oxidative metabolism may provide a protective effect by increasing ATP synthesis per unit substrate and prevent glycolysis-mediated acidosis and subsequent cell death upon transplantation into the glucose-and oxygen-deprived environment of the infarcted heart.
BACKGROUND: Cell-based therapies show promise in repairing cardiac tissue and improving contractile performance following a myocardial infarction. Despite this, ischemia-induced death of transplanted cells remains a major hurdle to the efficacy of treatment. 'Superhealer' MRL/MpJ mesenchymal stem cells (MRL-MSCs) have been reported to exhibit increased engraftment resulting in reduced infarct size and enhanced contractile function. This study determines whether intrinsic differences in mitochondrial oxidative phosphorylation (OXPHOS) assist in explaining the enhanced cellular survival and engraftment of MRL-MSCs. FINDINGS: Compared to wild type MSCs (WT-MSCs), mitochondria from intact MRL-MSCs exhibited an increase in routine respiration and maximal electron transport capacity by 2.0- and 3.5-fold, respectively. When routine oxygen utilization is expressed as a portion of maximal cellular oxygen flux, the MRL-MSCs have a greater spare respiratory capcity. Additionally, glutamate/malate succinate-supported oxygen consumption in permeabilized cells was elevated approximately 1.25- and 1.4-fold in the MRL-MSCs, respectively. CONCLUSION: The results from intact and permeabilized MSCs indicate MRL-MSCs exhibit a greater reliance on and capacity for aerobic metabolism. The greater capacity for oxidative metabolism may provide a protective effect by increasing ATP synthesis per unit substrate and prevent glycolysis-mediated acidosis and subsequent cell death upon transplantation into the glucose-and oxygen-deprived environment of the infarcted heart.
Authors: Maria P Alfaro; Alicia Vincent; Sarika Saraswati; Curtis A Thorne; Charles C Hong; Ethan Lee; Pampee P Young Journal: J Biol Chem Date: 2010-09-07 Impact factor: 5.157
Authors: Simon Lord-Dufour; Ian B Copland; Louis-Charles Levros; Martin Post; Abhirup Das; Chaitan Khosla; Jacques Galipeau; Eric Rassart; Borhane Annabi Journal: Stem Cells Date: 2009-03 Impact factor: 6.277
Authors: Maria P Alfaro; Matthew Pagni; Alicia Vincent; James Atkinson; Michael F Hill; Justin Cates; Jeffrey M Davidson; Jeffrey Rottman; Ethan Lee; Pampee P Young Journal: Proc Natl Acad Sci U S A Date: 2008-11-18 Impact factor: 11.205
Authors: M Deschepper; K Oudina; B David; V Myrtil; C Collet; M Bensidhoum; D Logeart-Avramoglou; H Petite Journal: J Cell Mol Med Date: 2011-07 Impact factor: 5.310