1. Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration
- Author
-
Giuseppe Vassalli, Giovanni G. Camici, Sara Bolis, Elisabetta Cervio, Giuseppina Milano, Vanessa Biemmi, A. Ciullo, Tiziano Moccetti, Emanuel T. Fertig, Lucio Barile, Mihaela Gherghiceanu, University of Zurich, and Barile, Lucio
- Subjects
0301 basic medicine ,Male ,Benzylamines ,Myocardial Infarction ,1607 Spectroscopy ,Fluorescent Antibody Technique ,Pharmacology ,Cyclams ,Cell therapy ,lcsh:Chemistry ,0302 clinical medicine ,Heterocyclic Compounds ,intravenous injection ,Myocardial infarction ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,Ejection fraction ,General Medicine ,Flow Cytometry ,3. Good health ,Computer Science Applications ,030220 oncology & carcinogenesis ,10209 Clinic for Cardiology ,Systemic administration ,1606 Physical and Theoretical Chemistry ,Cardiac function curve ,Receptors, CXCR4 ,1503 Catalysis ,Cell Survival ,Blotting, Western ,Ischemia ,cardiac progenitor cells ,610 Medicine & health ,Enzyme-Linked Immunosorbent Assay ,macromolecular substances ,exosomes ,11171 Cardiocentro Ticino ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Animals ,Cell Survival/drug effects ,Cell Survival/genetics ,Cell Survival/physiology ,Chemokine CXCL12/genetics ,Chemokine CXCL12/metabolism ,Cryoelectron Microscopy ,Exosomes/metabolism ,Heterocyclic Compounds/therapeutic use ,Humans ,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 ,1312 Molecular Biology ,1706 Computer Science Applications ,medicine ,RNA, Messenger ,Physical and Theoretical Chemistry ,Progenitor cell ,Molecular Biology ,1604 Inorganic Chemistry ,business.industry ,Organic Chemistry ,fungi ,medicine.disease ,Chemokine CXCL12 ,carbohydrates (lipids) ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,business ,Reperfusion injury ,1605 Organic Chemistry - 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 ExoCXCR4 significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to ExoCTRL (p <, 0.01). Hemodynamic measurements showed that ExoCXCR4 improved dp/dt min, as compared to ExoCTRL and PBS group. In vitro, ExoCXCR4 was more bioactive than ExoCTRL 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.
- Published
- 2019