Abstract 11164: Resetting Aging Clock in the Senescent Stem Cells by Suppressing Microrna-146a Promotes Cardiomyogenesis in the Ischemic Heart
Background: Stem cell-mediated cardiac repair is impaired with aging. Previously, we found that age-induced microRNA (miR)-146a was significantly increased in aged bone marrow stem cells (BMSCs) as compared to small juvenile cells present in bone marrow of aging animals. In this study, we hypothesized that age-induced miR-146a regulates stem cell function for cardiac repair.
Methods and Results: Computational analysis and luciferase assay confirmed that miR-146a directly targets 3’ untranslated region of Notch1 gene, and transfection of anti-miR-146a significantly inhibited Notch1 protein expression in aged BMSCs (2.5 fold increase). Interestingly, knockdown of miR-146a significantly increased expression of cardiac lineage markers including Gata4, Nkx2.5 and Mef2c and decreased senescence-associated β-galactosidase expression in aged BMSCs, suggesting miR-146a is involved in stem cell aging by targeting Notch1. To investigate potential role of miR-146a in stem cell function for cardiac repair, we injected 2x104 of BMSCs transfected with miR-146a inhibitor or scramble control into the infarcted heart using mouse left anterior descending artery (LAD) ligation model. At 4 weeks after cell transplantation, LVEF, LVFS and LVEDV were significantly improved by transplantation of anti-miR-146a transfected group (43.9±4.6 vs 34.7±2.5%, 22.4±4.4 vs 15.4±2.3%, 82.6±4.2 vs 161.7±5.3 mm3, p<0.05, n=6, respectively) as evaluated by echocardiography. In addition, systolic function as well as diastolic function as assessed by E/E’ (17.4±1.8 vs 24.7±0.9, p<0.05) and cardiac performance index (0.29±0.05 vs 0.54±0.04, p<0.05) which are used for prognosis of heart failure were significantly improved by transplantation of anti-miR-146a transfected group. Immunohistochemical analysis demonstrated that transplantation of BMSCs lacking miR-146a increased angiomyogenesis and reduced TUNEL-positive apoptotic cells in peri-infarct area.
Conclusions: Upregulation of miR-146a contributes to stem cell aging and impairs cardiomyogenic potential by targeting Notch1. This study demonstrated that aging clock in stem cells can be reversed by miR-146a suppression, thereby restoring stem cell function for angiomyogenesis in the ischemic heart.
- © 2013 by American Heart Association, Inc.