Functional Consequences of Human Induced Pluripotent Stem Cells Therapy: Myocardial ATP Turnover Rate in the in vivo Swine Hearts with Post-Infarction Remodeling
Background—The use of cells derived from hiPSCs as cellular therapy for myocardial injury has yet to be examined in a large-animal model.
Methods and Results—Immuno-suppressed Yorkshire pigs were assigned to one of three groups; MI: distal LAD ligation and reperfusion (n=13), CELL: MI with 4x106 hiPSC-VCs administered via a fibrin patch (n=14), Normal (n=15). At 4 weeks, LV structural and functional abnormalities were less pronounced in CELL hearts than in MI hearts (p<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% vs. 8.3±1.1%; MI vs CELL, p<0.05). CELL was associated with significant increase of vascular density and blood flow (0.83±0.11 and 1.05±0.13 ml/min per g, MI vs. CELL, p<0.05) in the peri-scar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (IZ: -10±7% vs. 5±5%; BZ: 7±4% vs. 23±6%; p<0.05). hiPSC-VC transplantation stimulated c-kit+ cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit+ cells and cardiomyocytes (p<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, p<0.05). This decline in BZ ATP utilization was markedly attenuated in the CELL group.
Conclusions—hiPSC-VC transplantation mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases of BZ contractile function and ATP turnover rate.
- Received December 21, 2012.
- Revision received January 15, 2013.
- Accepted January 18, 2013.
- Copyright © 2013, Circulation