Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction

Eur Heart J. 2017 Jan 14;38(3):201-211. doi: 10.1093/eurheartj/ehw240.


Aims: Naturally secreted nanovesicles known as exosomes are required for the regenerative effects of cardiosphere-derived cells (CDCs), and exosomes mimic the benefits of CDCs in rodents. Nevertheless, exosomes have not been studied in a translationally realistic large-animal model. We sought to optimize delivery and assess the efficacy of CDC-secreted exosomes in pig models of acute (AMI) and convalescent myocardial infarction (CMI).

Methods and results: In AMI, pigs received human CDC exosomes (or vehicle) by intracoronary (IC) or open-chest intramyocardial (IM) delivery 30 min after reperfusion. No-reflow area and infarct size (IS) were assessed histologically at 48 h. Intracoronary exosomes were ineffective, but IM exosomes decreased IS from 80 ± 5% to 61 ± 12% (P= 0.001) and preserved left ventricular ejection fraction (LVEF). In a randomized placebo-controlled study of CMI, pigs 4 weeks post-myocardial infarction (MI) underwent percutaneous IM delivery of vehicle (n = 6) or CDC exosomes (n = 6). Magnetic resonance imaging (MRI) performed before and 1 month after treatment revealed that exosomes (but not vehicle) preserved LV volumes and LVEF (−0.1 ± 2.2% vs. −5.4 ± 3.6%, P= 0.01) while decreasing scar size. Histologically, exosomes decreased LV collagen content and cardiomyocyte hypertrophy while increasing vessel density.

Conclusion: Cardiosphere-derived cell exosomes delivered IM decrease scarring, halt adverse remodelling and improve LVEF in porcine AMI and CMI. While conceptually attractive as cell-free therapeutic agents for myocardial infarction, exosomes have the disadvantage that IM delivery is necessary.

MeSH terms

  • Acute Disease
  • Animals
  • Chronic Disease
  • Cicatrix / prevention & control*
  • Disease Models, Animal
  • Exosomes / transplantation*
  • Female
  • Magnetic Resonance Angiography
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy*
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • Neovascularization, Physiologic / physiology
  • Random Allocation
  • Regeneration / physiology
  • Spheroids, Cellular / metabolism
  • Swine
  • Swine, Miniature
  • Ventricular Function / physiology
  • Ventricular Remodeling / physiology