Abstract 11298: Aged Human Cells Rejuvenated by Cytokine-Enhancement of Biomaterials for Surgical Ventricular Restoration
Background: Stem cell exhaustion contributes to the increased risk of heart failure in the elderly following a myocardial infarction (MI). New therapies are urgently needed to rejuvenate their dysfunctional stem cells and prevent ventricular decompensation. We created a cell-seeded, cytokine-enhanced biodegradable cardiac patch to restore a normal size and shape to the infarcted ventricle by surgical ventricular restoration (SVR). The sustained cytokine release was intended to rejuvenate human stem cells from old patients, to prevent remodeling and improve ventricular function in an animal MI model.
Methods/Results: We covalently immobilized two pro-angiogenic cytokines, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), onto porous collagen scaffolds. The scaffolds were seeded with human mesenchymal stem cells (MSCs) isolated from young (50.0±8.0 years, N=4) or old (74.5±7.4 years, N=4) cardiac surgery patients. In vitro cell proliferation was lowest in MSCs seeded in cytokine-free scaffolds, but was significantly increased with cytokine enhancement (p<0.05 day 2, p<0.01 day 4), similar to young cells. Cytokine enhancement also modulated the aging-related p16 gene, converting the old MSC phenotype to a young cell phenotype. We then evaluated the patches for SVR in a rat MI model. Cytokine enhancement significantly increased old MSC survival (p<0.05). Vascular density, determined by immunostaining of heart sections, was also significantly increased with the addition of cytokines to old MSCs (p<0.05). The patched area dramatically dilated on day 28 with old MSCs, but cytokine enhancement preserved the area similar to patches seeded with young cells (p<0.05). Cardiac function (assessed by echocardiography and pressure-volume loops) was best in rats with cytokine-enhanced patches. Ejection fraction was significantly lower (p<0.05) in rats implanted with old MSC-seeded patches (24.08±3.96%) vs. cytokine-enhanced old MSC-seeded patches (29.82±2.55%). Patches seeded with rejuvenated old MSCs became an elastic tissue.
Conclusion: This new platform for engineering myocardial tissue promises to rejuvenate old stem cells and prevent progressive heart failure.
- © 2012 by American Heart Association, Inc.