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

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.

TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis

“…However, little has been done about the distribution pattern of primed EVs in inflamed colon of murine model. Some studies have shown that EVs generated from priming stem cells reach more damaged tissues, increasing the protection effect 37 . However, unlike other studies, this study demonstrated that similar amount of primed EVs and naïve EVs have been found in colon, and that primed EVs is very effective in mitigating inflammation.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…The surface protein defined as pregnancy-associated plasma protein-A (PAPP-A) was found to be associated within CPC-EV as master regulator responsible for the release of active IGF factor leading to activation of pro-survival pathways involving phosphorylation of ERK1/2 and Akt in recipient cells [155]. In a preclinical rat model of acute myocardial infarction (MI), CPC-EVs injected into the infarct border zone or systemically injected via tail vein increased viable mass and vessel density, resulted in a diminished scar and improved global heart function [154,156]. Ibrahim et al showed that CDC-EVs were enriched in miRNA146a-5p.…”

“…Several studies have been lately reported suggesting alternative strategies to functionalise EVs for more accurate targeting of the damaged heart [220,221]. These include: lentiviral vector-based engineering of secreting cells to upregulate the expression of cardiomyocyte-specific binding peptides fused to the murine transmembrane protein Lamp2b, in order to enrich the targeting epitope on the exosomal surface [222]; overexpression of exosomal CXCR4 to push their bioavailability towards the ischaemic heart [156]; membrane anchoring systems to directly dock tissue-specific antibodies or homing antigens on the EV surface [223,224].…”

Turning regenerative technologies into treatment to repair myocardial injuries

“…Exosome‐producing cells can be molecularly engineered to enrich the presence of specific molecules on the exosome surface in order to target damaged myocardium. Exosomes derived from CPCs engineered to overexpress CXCR4, a receptor of the chemokine stromal cell‐derived factor 1 (SDF‐1), increase myocardium homing and cardioprotective effects in a rat model of ischaemia/reperfusion injury after systemic delivery . The enrichment in ligands can also be achieved by directly conjugating a synthetic myocardium targeting peptide, such as the cardiac homing peptide (CHP), to the surface of intravenously infused CSC‐derived exosomes .…”

“…Exosomes derived from CPCs engineered to overexpress CXCR4, a receptor of the chemokine stromal cell-derived factor 1 (SDF-1), increase myocardium homing and cardioprotective effects in a rat model of ischaemia/reperfusion injury after systemic delivery. 125 The enrichment in ligands can also be achieved by directly conjugating a synthetic myocardium targeting peptide, such as the cardiac homing peptide (CHP), to the surface of intravenously infused CSC-derived exosomes. 126 In addition, cells labelled with superparamagnetic nanoparticle can be guided to the injury site by an external magnetic field placed above the heart during the injection enhancing the retention/engraftment in the damaged area and multiplying the therapeutic benefit.…”