Abstract 9748: In Vivo Cardiac Cellular Reprogramming Efficacy is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium
A new in situ cellular reprogramming strategy demonstrated to convert fibroblasts into cardiomyocytes may represent an ideal cardiac regenerative therapy, obviating challenges inherent in stem cell implantation. We hypothesized that this strategy would be enhanced by angiogenic pretreatment of myocardial scar targeted by this treatment.
Methods: The efficacy of lentivirus-mediated delivery of Gata4, Mef 2c and Tbx5 to transdifferentiate rat fibroblasts into induced cardiomyocytes (iCMs; Ieda et. al., Cell. 2010; 142: 375-386) was validated by in vitro FACS and immunofluorescence studies. Adult male Fischer 344 rats (n=12/group) then underwent coronary ligation and intramyocardial administration of AdVEGF-All6A+, an adenovirus encoding all three major isoforms of VEGF, or AdNull, an empty expression cassette vector. Three wks later, 6 animals/group received lentiviruses each encoding Gata4, Mef 2c or Tbx5 (GMT), or encoding only GFP. Echocardiograms were performed prior to and 3d after coronary ligation, at the time of GMT or GFP administration (baseline), and 2 and 4 wks later.
Results: In vitro studies demonstrated rat fibroblast conversion into iCMs based on cellular morphology and expression of markers including cardiac troponin T. Echo analyses in the myocardial infarction model above demonstrated significant improvement from baseline for cardiac ejection fraction (EF) 2 and 4 wks after GMT vs GFP administration (EF% change 4 wks after treatment: 12% ± 9% vs -7% ± 10%, p<0.01). Eight GFP-treated but no GMT animals demonstrated decreased EF during this interval (p<0.01). Moreover, improvement in EF was 4 times greater in GMT/VEGF vs GMT/AdNull animals (17% ± 7 % vs 4% ± 3%, p<0.01). No significant change in EF was detected in animals treated with AdVEGF-All6A+ without GMT.
Conclusion: Angiogenic pretreatment of myocardial scar significantly enhances the efficacy of cellular reprogramming after myocardial infarction.
- © 2012 by American Heart Association, Inc.