These results suggest that CPC-secreted exosomes may be more cardioprotective than BMC-secreted exosomes, and that PAPP-A-mediated IGF-1 release may explain the benefit. They illustrate a general mechanism whereby exosomes may function via an active protease on their surface, which releases a ligand in proximity to the transmembrane receptor bound by the ligand.
Background Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents. Methods We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia ( n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA. Findings Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels. Interpretation In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity. Funding Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.
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.
Aims -Circulating extracellular vesicles (EV) are raising considerable interest as a non-invasive diagnostic tool as they are easily detectable in biological fluids and contain specific set of nucleic acids, proteins, and lipids reflecting pathophysiological conditions. We aimed to investigate differences in plasma-derived EV surface-protein profile as biomarker to be used in combination with endomyocardial biopsies (EMB) for the diagnosis of allograft rejection.Methods and results -Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) prior to EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay comprising 37 fluorescently labelled capture bead populations coated with specific antibodies directed against respective EV surface epitopes. The concentration of EV was significantly increased and their diameter decreased in patients undergoing rejection as compared to negative ones. The trend was highly significant for both antibody-mediated rejection (AMR), and acute cellular rejection (P<0.001). Among EV-surface markers, CD3, CD2, ROR1, SSEA-4, HLA-I, and CD41b were identified as discriminants between controls and ACR, whereas HLA-II, CD326, CD19, CD25, CD20, ROR1, SSEA-4, HLA-I, and CD41b discriminated controls from patients with AMR. ROC curves confirmed a reliable diagnostic performance for each single marker (AUC range 0.727-0.939). According to differential EV-marker expression, a diagnostic model was built and validated in an external cohort of patients. Our model was able to distinguish patients undergoing rejection from those without rejection. The accuracy at validation in an independent external cohort reached 86.5%. Its application for patient management has the potential to reduce the number of EMBs.Further studies in a higher number of patients are required to validate this approach for clinical purpose.Conclusions -Circulating EV are highly promising as new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring. 2NARRATIVE ABSTRACT -Our study describes a method for detecting and characterising circulating extracellular vesicles (EV) as a minimally invasive, liquid biopsy for the diagnosis of cardiac allograft rejection, and as a complementary tool to EMB monitoring. EV obtained from peripheral blood were profiled to identify rejection and its types in cardiac transplant recipients. A standardized and rapid tool was established using a fluorescent bead-based multiplex assay. We built a diagnostic model based on machine learning algorithms to identify non-rejecting patients who potentially do not require EMBs. EV profiling could represent a tool for non-invasive monitoring of allograft rejection in cardiac transplant recipients.
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