Cell-based therapies show promise in repairing cardiac tissue and improving contractile performance

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* Corresponding author: Curtis C Hughey cchughey@ucalgary.ca
The electronic version of this article is the complete one and can be found online at: http://www.cellregenerationjournal.com/content/1/1/3 Received: 8 July 2011 Accepted: 28 June 2012 Published: 28 June 2012
This is an Open Access article rspca vets distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original rspca vets work is properly cited.
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 rspca vets survival and engraftment of MRL-MSCs. Findings
Compared to wild type MSCs (WT-MSCs), mitochondria from intact rspca vets 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 rspca vets flux, the MRL-MSCs have a greater rspca vets spare respiratory capcity. Additionally, glutamate/malate- and succinate-supported oxygen consumption in permeabilized cells was elevated approximately 1.25- and 1.4-fold in the MRL-MSCs, respectively. Conclusion
The rspca vets 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 rspca vets per unit substrate and prevent glycolysis-mediated acidosis and subsequent cell death upon transplantation rspca vets into the glucose-and oxygen-deprived environment of the infarcted heart. Keywords: Energetics; Mitochondria; Oxidative phosphorylation; Stem cells Findings
Advances in stem cell therapy for treating a myocardial infarction (MI) are impeded by inadequate survival and engraftment of implanted cells in the host tissue. Up to 99% of mesenchymal stem cells (MSCs) experience cell death following rspca vets administration into the infarcted heart [ 1 , 2 ]. A predominant factor for the poor survival is ischemia [ 3 , 4 ]. Ischemia results in ATP depletion, a reduction in mitochondrial oxidative phosphorylation (OXPHOS) and increased reliance on glycolysis leading to cellular acidosis and cell death [ 4 ].
The bone marrow-derived Superhealer MRL/MpJ MSC (MRL-MSC) has been reported to exhibit greater engraftment in the infarcted heart [ 5 ]. This improved retention promotes superior cardio-protection as indicated by increased angiogenesis, reduced infarct size and improved contractility in a murine MI model [ 5 ]. The primary contributor of MRL-MSC-mediated wound repair and cardiac contractile improvements was identified as the paracrine/autocrine factor, secreted frizzled related receptor protein 2 (sFRP2) [ 5 , 6 ]. sFRP2 is a member of the sFRP family that exhibits a cysteine-rich domain that binds Wnt glycoproteins [ 7 ]. sFRP binding diminishes Wnt interactions with frizzled receptors, which propagate apoptosis through the canonical β-catenin rspca vets pathway [ 8 ]. In addition to its involvement in apoptosis, Wnt/β-catenin signaling promotes a switch in glucose metabolism from OXPHOS to glycolysis [ 9 ].
Given the infarcted region of the heart receives impaired oxygen and nutrient supply, the current study evaluates MSC OXPHOS to determine whether innate differences in the MRL-MSC oxygen utilization and mitochondrial energetics could explain their enhanced viability. Methods
Procedures were approved by the University of Calgary and Vanderbilt University Animal Care and Use Committees. Murine WT- and MRL-MSCs were generated and expanded rspca vets from C57BL6 and MRL/MpJ strains, respectively, as described [ 5 , 10 ]. Briefly, WT- and MRL-MSCs were cultured in a humidified atmosphere containing rspca vets 5% CO 2 at 37 C in low glucose Dulbecco s Modified Eagle Medium (DMEM; GIBCO) containing 1000 mg/L glucose, 110 mg/L sodium pyruvate, 10% defined fetal bovine serum (FBS; HyClone), 10% penicillin-streptomycin, 10% fungizone and 10 μg/L platelet-derived growth factor-ββ (PDGF-ββ; R&D Systems). The immuno