Abstract 11970: Sirtuin1 is a Key Regulator of Enhanced Therapeutic Potential in Juvenile Skeletal Myoblast Sheet Therapy for Treating Heart Failure
Introduction: Transplantation of autologous somatic tissue-derived stem cells into the heart has been shown to be therapeutically effective for heart failure in adult, though efficacy of this treatment for pediatric patients are poorly established. It is known that juvenile cell behave differently from adult one, associated with expression of aging-related factors such as sirtuin family.
Hypothesis: Sirtuin 1 expression is a key regulator of differential therapeutic potentials between juvenile and adult skeletal cells (SCs) for treating heart failure.
Methods and Results: Sirtuin 1 knock down (SIRT1-KD) was induced by RNA interference in primary SCs from Lewis rat. The SIRT1-KD SCs showed a longer doubling time, associated with lower expression of VEGF, HGF, and SDF-1, compared to the primary SCs in vitro. Cell-sheets generated by SIRT1-KD SCs or primary SCs were transplanted over the heart surface of the syngeneic Lewis rat that was subjected to left coronary artery (LCA) ligation 2 weeks prior to the treatment (n=5 each). As a result, recovery of ejection fraction was significantly less prominent in the SIRT1-KD group (31.6%) than the primary group (46.9%), in association with degree of histological ventricular remodeling, such as %fibrosis, myocyte size, or capillary density. Subsequently, autologous SC cell-sheet were cardiac-transplanted in 2-month-old juvenile and 20-30 month-old adult mini-pigs that were subjected to ischemia-reperfusion in the LCA territory (n=5 each). The juvenile porcine SCs displayed significantly shorter doubling time and greater Ki67-positivity, in association with up-regulated SIRT1, HIF-1α, HGF, and SDF-1, in vitro. At 2 months after the transplantation, recovery of EF was more prominent in the juvenile group (23.6% to 49.8%) than the adult group (28.8% to 36.2%). Moreover, regional wall motion (%strain) of the infarct-border area more prominently recovered in the juvenile group (-3.6% to -16.1%) than the adult group (-3.3% to -5.4%).
Conclusions: Juvenile SCs exhibited an enhanced therapeutic potential in association with upregulated expression of SIRT1 as compared to the adult SCs, suggesting that autologous cell-sheet transplantation may be therapeutically more effective for pediatric cardiomyopathy.
Author Disclosures: H. Ozawa: None. S. Miyagawa: None. S. Fukushima: None. A. Harada: None. E. Ito: None. A. Saito: None. T. Ueno: None. K. Toda: None. T. Kuratani: None. Y. Sawa: None.
- © 2015 by American Heart Association, Inc.