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

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_B4D231EB785E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration.
Journal
International journal of molecular sciences
Author(s)
Ciullo A., Biemmi V., Milano G., Bolis S., Cervio E., Fertig E.T., Gherghiceanu M., Moccetti T., Camici G.G., Vassalli G., Barile L.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Publication state
Published
Issued date
22/01/2019
Peer-reviewed
Oui
Volume
20
Number
3
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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 <sup>CXCR4</sup> significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo <sup>CTRL</sup> (p < 0.01). Hemodynamic measurements showed that Exo <sup>CXCR4</sup> improved dp/dt min, as compared to Exo <sup>CTRL</sup> and PBS group. In vitro, Exo <sup>CXCR4</sup> was more bioactive than Exo <sup>CTRL</sup> 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.
Keywords
Animals, Blotting, Western, Cell Survival/drug effects, Cell Survival/genetics, Cell Survival/physiology, Cells, Cultured, Chemokine CXCL12/genetics, Chemokine CXCL12/metabolism, Cryoelectron Microscopy, Enzyme-Linked Immunosorbent Assay, Exosomes/metabolism, Flow Cytometry, Fluorescent Antibody Technique, Heterocyclic Compounds/therapeutic use, Humans, Male, Myocardial Infarction/genetics, Myocardial Infarction/metabolism, Myocardial Infarction/therapy, RNA, Messenger/genetics, RNA, Messenger/metabolism, Rats, Rats, Wistar, Receptors, CXCR4/antagonists & inhibitors, Receptors, CXCR4/genetics, Receptors, CXCR4/metabolism, CXCR4, cardiac progenitor cells, exosomes, intravenous injection
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2019 12:25
Last modification date
20/08/2019 15:23
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