Header

UZH-Logo

Maintenance Infos

Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration


Ciullo, Alessandra; Biemmi, Vanessa; Milano, Giuseppina; Bolis, Sara; Cervio, Elisabetta; Fertig, Emanuel Tudor; Gherghiceanu, Mihaela; Moccetti, Tiziano; Camici, Giovanni G; Vassalli, Giuseppe; Barile, Lucio (2019). Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration. International Journal of Molecular Sciences, 20(3):E468.

Abstract

Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of Exo significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo ( < 0.01). Hemodynamic measurements showed that Exo improved dp/dt min, as compared to Exo and PBS group. In vitro, Exo was more bioactive than Exo in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.

Abstract

Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of Exo significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo ( < 0.01). Hemodynamic measurements showed that Exo improved dp/dt min, as compared to Exo and PBS group. In vitro, Exo was more bioactive than Exo in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.

Statistics

Citations

Dimensions.ai Metrics
32 citations in Web of Science®
28 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

28 downloads since deposited on 23 Oct 2019
13 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Cardiocentro Ticino
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Physical Sciences > Catalysis
Life Sciences > Molecular Biology
Physical Sciences > Spectroscopy
Physical Sciences > Computer Science Applications
Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Organic Chemistry
Physical Sciences > Inorganic Chemistry
Language:English
Date:22 January 2019
Deposited On:23 Oct 2019 13:20
Last Modified:16 Apr 2020 00:06
Publisher:MDPI Publishing
ISSN:1422-0067
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.3390/ijms20030468
PubMed ID:30678240

Download

Gold Open Access

Download PDF  'Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration'.
Preview
Content: Published Version
Filetype: PDF
Size: 4MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)