Na?ve exosomes released directly from parental cells might exert protective and regenerative effects on recipient cells, and those derived from immune cells are more likely to possess immune-modulating abilities (40), which implies their therapeutic potential for moderating immune responses elicited in cardiovascular diseases. pathological states, whether similar to or different from their parent cells. However, the underlying mechanism remains obscure. In this review, we first describe the biological characteristics and biogenesis of exosomes. Then we critically examine the emerging roles of exosomes in cardiovascular disease; the exosomes we focus on are derived from immune cells such as dendritic cells, macrophages, B cells, T cells, as well as neutrophils and mast cells. Among the cardiovascular diseases we discuss, we mainly focus on myocardial infarction and atherosclerosis. As active intercellular communicators, exosomes from immune cells may offer prospective diagnostic and therapeutic value in cardiovascular disease. V+Stable coronary artery diseasePrognostic (32)EndotheliumCD144+Stable patients at high risk for coronary heart diseasePrognostic (33)SerummiR-192, miR-194, miR-34aHeart failure after acute myocardial infarctionPrognostic (34) Open in a separate window Pros and Cons of Exosomal Biomarkers Over Conventional Biomarkers Testing exosomal biomarkers has been described as a form of liquid biopsy (36) that is less invasive and risky. Exosomes are similar to their cells of origin in some common markers, while they differ from parental cells and constantly alter the proportion of certain contents under different pathophysiological situations, which increases the accuracy of diagnosis at the molecular and cellular level. Thus, exosomes derived from immune cells can be considered convenient carriers that contain constitutively expressed immune system-specific proteins and nucleic acids that can be employed for the detection of immunologic status in cardiovascular diseases. Exosomes as well as their cargo including miRNAs that are usually prone to rapid degradation by RNAses (37) are stable over a period of time, allowing for the isolation and analysis of these miRNAs for diagnostic/prognostic purposes. The stability of exosomes and the protection of the cargo from degradation allows to isolate and analyze exosomes from multiple sources including blood, pericardial fluid, lymphatic fluid, and urine (36). However, there are several technical limitations for clinical translation of exosomal biomarkers at present. The primary factor that hinders the clinical use is the lack Hoechst 33258 analog 5 of standardized pre-analytical and isolation procedures (36). Various isolation methods for exosomes have been adopted for research, but there is no possible method for the clear classification of all subpopulations of exosomes, and none of them is officially recognized and suitable for convenient and quick clinical testing. Utilizing different approaches to isolate exosomes from different originating cells and sources of fluids, it is tough to set convincing reference ranges under various circumstances. In addition, confounding factors like disease specificity and the presence of comorbidities and medications may have an influence on the level of exosomal biomarkers (36). More importantly, it remains to be further validated whether exosomes possess diagnostic and prognostic value for a large number of patients (38), and whether exosomes can provide additional value over current biomarkers that are widely and clinically adopted. The Potential of Exosomes as Therapeutics in Cardiovascular Diseases Preclinical studies have demonstrated the protective effects of exosomes in ischemic heart diseases via alleviating myocardial ischemia-reperfusion injury, and by promoting angiogenesis and cardiac regeneration (39). Generally, exosome-based therapies can be divided into two categories according to whether modifications or drugs are added (Figure 2). Na?ve exosomes released directly from parental cells may exert protective and regenerative effects on recipient cells, and those derived from immune cells are more likely to possess immune-modulating abilities (40), which implies their therapeutic potential for moderating immune responses elicited in cardiovascular diseases. However, it is difficult to manipulate na?ve exosomes because of their multiple biological effects, thus an increasing Hoechst 33258 analog 5 number of researchers have been attempting to rebuild exosomes by incorporating low-molecular-weight drugs or by modifying their parental cells (40). Exosomes Hoechst 33258 analog 5 can be loaded IKK-gamma antibody with drugs by incubation at room temperature, electroporation, and mild sonication (41), which surprisingly enhances the efficacy and release efficiency of drugs. Furthermore, pretreatment of parental cells with therapeutic agents and genetic modification of donor cells may help in targeting exosomes to lesions and have been shown to efficiently deliver exosomes with specific modifications (41). Open in a separate window Figure 2 The potential use of exosome-based therapies in cardiovascular diseases. Exosomes used as therapeutics are usually isolated from cell culture experiments creating miR-155-deficient mice, which.