Abstract 10697: Microrna 195 Overexpression in Aging Deteriorates Stem Cell Function for Cardiac Repair by Deactivating Telomerase
Background: Decline in stem cell function aggravates aging process. Recently, we found age-induced microRNA (miR)-195 targets telomerase reverse transcriptase (TERT) in bone marrow-derived mesenchymal stem cells (BMSCs), and inhibition of miR-195 induced telomere re-lengthening in aged BMSCs. However, the effect of miR-195 on stem cell function and in cardiac repair is unknown.
Methods and Results: To investigate the potential role of miR-195 in stem cell function, we transfected aged BMSCs isolated from aged mice (24 months) with lentiviral anti-miR-195 to knockdown miR-195 expression. Inhibition of miR-195 significantly reactivated anti-aging factors including Tert and Sirt1 along with telomere re-lengthening in aged BMSCs. To further confirm that miR-195 inhibition restores angiomyogenic potential of aged BMSCs, we injected 2x104 of BMSCs transfected with miR-195 inhibitor into the infarcted heart using mouse left anterior descending artery (LAD) ligation model. At 4 weeks after transplantation, LVEF, LVFS and LVEDV were significantly improved in transplantation of anti-miR-195 transfected group (49.5±8.3 vs 34.7±7.7%, 34±4.7 vs 15.3±5.5%, 88.6±17.0 vs 161.6±25.6 mm3, p<0.05, n=6, respectively) as compared to scramble control group, as assessed by echocardiography. Not only systolic function but also diastolic function such as E/E’ (15.3±1.0 vs 24.8±2.9, p<0.05) and cardiac performance index (0.28±0.07 vs 0.54 ±0.34, p<0.05) were significantly improved by transplantation of anti-miR-195 transfection. Histological analysis of anti-miR-195 transfected group indicated less fibrosis and smaller infarction size along with higher angiomyogenesis as compared to control group. Moreover, significant telomere lengthening (Q-FISH analysis) and higher expression of anti-aging factors were observed in the heart lacking miR-195 (RT-PCR and Western blot).
Conclusions: Inhibition of age-induced miR-195 significantly restored telomerase expression in aged BMSCs, and transplantation of BMSCs lacking miR-195 improved cardiac function. The ability to use autologous, rejuvenated aged BMSCs by miR-195 inhibition is a novel therapeutic strategy for aging myocardium suffering from myocardial infarction.
- © 2013 by American Heart Association, Inc.