serval:BIB_B4D231EB785E
Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration.
10.3390/ijms20030468
000462412500012
30678240
Ciullo
A.
author
Biemmi
V.
author
Milano
G.
author
Bolis
S.
author
Cervio
E.
author
Fertig
E.T.
author
Gherghiceanu
M.
author
Moccetti
T.
author
Camici
G.G.
author
Vassalli
G.
author
Barile
L.
author
article
2019-01-22
International journal of molecular sciences
1422-0067
1422-0067
journal
20
3
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article
Publication Status: epublish
University of Lausanne
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