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.
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.
Authors: Vasiliy S Chernyshev; Rakesh Rachamadugu; Yen Hsun Tseng; David M Belnap; Yunlu Jia; Kyle J Branch; Anthony E Butterfield; Leonard F Pease; Philip S Bernard; Mikhail Skliar Journal: Anal Bioanal Chem Date: 2015-03-28 Impact factor: 4.142
Authors: Lucio Barile; Vincenzo Lionetti; Elisabetta Cervio; Marco Matteucci; Mihaela Gherghiceanu; Laurentiu M Popescu; Tiziano Torre; Francesco Siclari; Tiziano Moccetti; Giuseppe Vassalli Journal: Cardiovasc Res Date: 2014-07-11 Impact factor: 10.787
Authors: Tarun Chakravarty; Raj R Makkar; Deborah D Ascheim; Jay H Traverse; Richard Schatz; Anthony DeMaria; Gary S Francis; Thomas J Povsic; Rachel R Smith; Joao A Lima; Janice M Pogoda; Linda Marbán; Timothy D Henry Journal: Cell Transplant Date: 2016-08-18 Impact factor: 4.064
Authors: Konstantinos Malliaras; Raj R Makkar; Rachel R Smith; Ke Cheng; Edwin Wu; Robert O Bonow; Linda Marbán; Adam Mendizabal; Eugenio Cingolani; Peter V Johnston; Gary Gerstenblith; Karl H Schuleri; Albert C Lardo; Eduardo Marbán Journal: J Am Coll Cardiol Date: 2013-09-11 Impact factor: 24.094