Abstract 14423: Toll-like Receptor 3 Activation of Cardiosphere-Derived Cells (TLR3-CDCs) Amplifies Myocyte Regeneration and Reverses LV Remodeling in Swine With Ischemic Cardiomyopathy
Introduction: Intracoronary cardiosphere-derived cells (CDCs) administered to patients with myocardial infarction improves regional function through an effect that is secondary to the release of paracrine mediators that promote endogenous myocyte proliferation.
Hypothesis: We tested the hypothesis that amplifying CDC derived paracrine factors by activating toll-like receptor 3 (TLR3) on CDCs using polyinosine-polycytidylic acid ex vivo (40μg/ml for 24 hours) could improve functional recovery and more effectively stimulate endogenous myocyte proliferation.
Methods: Yorkshire swine (n=18) underwent a two-hour LAD occlusion and reperfusion to produce a healed myocardial infarct (post-MI ischemic cardiomyopathy). After one month, animals were started on cyclosporine (100 mg/day) and randomized to receive allogeneic TLR-CDCs, untreated CDCs or vehicle control infused slowly into the 3 major coronary distributions (total 20 x 106 cells). One month later, we assessed myocardial function (echocardiogram), infarct size (TTC), myocyte proliferation (Ki67) and myocyte nuclear density in each group.
Results: TLR3 activation upregulated HGF, IGF, IL-6 expression by 4 to 6-fold without affecting TNF-α and IL-1. TLR3-CDCs increased regional wall thickening and ejection fraction more than untreated CDCs with similar reductions in infract size. TLR3-CDCs stimulated myocyte proliferation (Ki67) in border and remote regions by 10-fold and myocyte number (nuclear density) increased by 2-fold in infarct border and remote regions.
Conclusions: Stimulation of TLR3 receptors upregulates growth factor expression in CDCs and increases myocardial function and myocyte proliferation more than CDCs alone. This suggests that modulating CDC paracrine factor release may enhance the functional effects of intracoronary CDCs in healed myocardial infarcts.
Author Disclosures: G. Suzuki: None. W.R. Brian: None. R.F. Young: None. J.M. Canty: None.
- © 2016 by American Heart Association, Inc.