Abstract 16991: Cardiosphere-derived Cell Exosomes Confer Acute Cardioprotection Following Ischemia-reperfusion Injury Through Macrophage Polarization (Best of Basic Science Abstract)
Introduction: Cardiosphere-Derived Cells (CDCs) exert both regenerative and cardioprotective effects following ischemic insult to the myocardium. The regenerative effects are mimicked by human CDC exosomes (CDCexo), secreted nanovesicular entities that contain CDC-specific payloads of protein and noncoding RNA. Here we demonstrate that, CDCexo reduce infarct size and macrophage (Mf) infiltration when infused via the intracoronary route following ischemia/reperfusion (I/R) injury.
Methods & Results: To examine the safety and efficacy of CDCexo, we performed a dose-finding study in Wistar-Kyoto rats (aged 8-12 weeks). Exosomes were precipitated from conditioned media collected from human CDCs or Fibroblasts [Fb, as a control] grown in serum-free media for 15 days. Exosome protein quantity, surface marker expression, and particle number were assessed prior to delivery. For in vivo analyses, rats underwent 45 minutes of ischemia followed by 20 minutes of reperfusion, then intracoronary infusion by random allocation of either Fb exosomes (Fbexo) or CDCexo. Two days later, histological analysis revealed that CDCexo reduced infarct mass (CDCexo: 6.38% vs. Fbexo: 13.32%; p<0.05) and CD68+ Mf infiltration (CDCexo: 183.5/FOV vs. Fbexo: 302.1/FOV; p<0.05). In vitro, Mf uptake of exosomes and polarization based on gene expression profile (Arg1, Vegfa, Il4ra) occurred in a time-dependent manner. The phagocytic capacity of CDCexo-primed Mf was elevated relative to Fbexo-, M1-, or M2-polarized Mf (CDCexo: 76.8%; Fbexo: 38.3%; M1: 52.2%; M2: 33.9%; p<0.05).
Conclusions: CDCexo are cardioprotective when delivered via the intracoronary route 20 min post-I/R. These data demonstrate that exosomes secreted by CDCs (but not by fibroblasts) recapitulate the cardioprotective effects of CDCs (cellular postconditioning; Kanazawa et al, Circ HF 2015; de Couto et al, JCI 2015). Like CDCs, CDCexo modulate the Mf infiltrate in the heart post-I/R and distinctively polarize Mf. The data support the conjecture that CDCexo mediate the cardioprotective effects of CDCs via effects on Mf.
Author Disclosures: G. de Couto: None. N. Makkar: None. E. Marbán: Consultant/Advisory Board; Significant; Capricor Inc..
- © 2015 by American Heart Association, Inc.