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Objectives: The aim of the current study was to evaluate the effect of recipient age on the regenerative response to implantation with young skeletal myoblasts (SKMCs) after a coronary artery ligation. Background: In contrast with previous findings in animals, the initial clinical trials of cell transplantation after a myocardial infarction have reported only limited improvements in ventricular function. The restricted regenerative capacity of cells isolated from older patients is certainly a factor; however, the present study investigated the impact of another potentially significant factor: recipient age. Methods: We compared the myogeneic capacities of SKMCs isolated from young rats (3 months old) and older rats (24 months old). Highly myogenic SKMCs derived from young rats (or culture media, in control rats) were then transplanted into the infarcted myocardium of young and older recipients at 1 week after coronary ligation. Results: In vitro, proliferation and myotube formation were significantly greater in SKMCs derived from young rats than from older rats. In vivo, young and older recipients of SKMCs exhibited increases in cell density, vascular density, and collagen preservation relative to age-matched control animals. However, cell therapy produced significantly greater functional improvements in young recipients than in older, along with relative increases in stem cell factor, cell density, cell survival, and angiogenesis. Conclusions: Functional improvement after the post–myocardial infarction implantation of young SKMCs was limited in older recipients, likely due to reductions in their cardiac and systemic responses to cell transplantation. [Copyright &y& Elsevier]

Background: Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)-related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta.Objectives: This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17-related miRNA regulation of TIMP-MMP.Methods: To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal.Results: Gene expression analyses confirmed increased expression of miR-17-related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-17 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression.Conclusions: Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17-related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated whether cytokine enhancement of a biodegradable patch could restore cardiac function after surgical ventricular restoration (SVR) even when seeded with cells from old donors. Background: SVR can partially restore heart size and improve function late after an extensive anterior myocardial infarction. However, 2 limitations include the stiff synthetic patch used and the limited healing of the infarct scar in aged patients. Methods: We covalently immobilized 2 proangiogenic cytokines (vascular endothelial growth factor and basic fibroblast growth factor) onto porous collagen scaffolds. We seeded human mesenchymal stromal cells from young (50.0 ± 8.0 years, N = 4) or old (74.5 ± 7.4 years, N = 4) donors into the scaffolds, with or without growth factors. The patches were characterized and used for SVR in a rat model of myocardial infarction. Cardiac function was assessed. Results: In vitro results showed that cells from old donors grew slower in the scaffolds. However, the presence of cytokines modulated the aging-related p16 gene and enhanced cell proliferation, converting the old cell phenotype to a young phenotype. In vivo studies showed that 28 days after SVR, patches seeded with cells from old donors did not induce functional recovery as well as patches seeded with young cells. However, cytokine-enhanced patches seeded with old cells exhibited preserved patch area, prolonged cell survival, and augmented angiogenesis, and rats implanted with these patches had better cardiac function. The patch became an elastic tissue, and the old cells were rejuvenated. Conclusions: This sustained-release, cytokine-conjugated system provides a promising platform for engineering myocardial tissue for aged patients with heart failure. [ABSTRACT FROM AUTHOR]