Salivary Exosomes: Emerging Roles in Systemic Disease

Abstract

Saliva, which contains biological information, is considered a valuable diagnostic tool for local and systemic diseases and conditions because, similar to blood, it contains important molecules like DNA, RNA, and proteins. Exosomes are cell-derived vesicles 30-100 nm in diameter with substantial biological functions, including intracellular communication and signalling. These vesicles, which are present in bodily fluids, including saliva, are released upon fusion of multivesicular bodies (MVBs) with the cellular plasma membrane. Salivary diagnosis has notable advantages, which include noninvasiveness, ease of collection, absence of coagulation, and a similar content as plasma, as well as increased patient compliance compared to other diagnostic approaches. However, investigation of the roles of salivary exosomes is still in its early years. In this review, we first describe the characteristics of endocytosis and secretion of salivary exosomes, as well as database and bioinformatics analysis of exosomes. Then, we describe strategies for the isolation of exosomes from human saliva and the emerging role of salivary exosomes as potential biomarkers of oral and other systemic diseases. Given the ever-growing role of salivary exosomes, defining their functions and understanding their specific mechanisms will provide novel insights into possible applications of salivary exosomes in the diagnosis and treatment of systemic diseases.

Keywords: biomarker; exosome; genomics; proteomics; saliva.

Figure 1

Exosome endocytosis and secretion. Early endosomes are formed after internalization when the receptor binds the ligand. Proteins in the early endosome can either be recycled to the plasma membrane or become part of the luminal vesicle (ILV) of multivesicular bodies (MVBs). ILVs of MVBs are generated by budding from the limiting membrane and enter the lumen of endosomes. Several molecules, such as RAB11 and RNA35, are involved in recycling and early sorting endosomes. MVBs can fuse with lysosomes or the plasma membrane, releasing their contents to the extracellular medium. RAB11 and RAB27 are linked with the late endosomal and secretory compartments. Neighboring cells can internalize the cytoplasmic contents of the exosomes, which can also mature into MVBs.

Figure 2

MicroRNA (miR)-21 in hypoxic oral squamous cell carcinoma (OSCC)-derived exosomes is significantly upregulated under hypoxic conditions, and the hypoxic microenvironment stimulates tumour cells to generate miR-21-rich exosomes to be delivered to normoxic cells to promote prometastatic behaviors. On the other hand, exosomes containing miR-21 target phosphatase and tensin homolog (PTEN), and programmed cell death protein 4 (PDCD4), exhibit cisplatin resistance in OSCC. Moreover, miR-200c-3p in exosomes derived from a highly invasive OSCC line can induce a similar phenotype in non-invasive counterparts to promote OSCC invasion. The expression of proteasome subunit α type 7 (PSMA7) in salivary exosomes in patients with inflammatory bowel disease (IBD) showed significant differences between patients with IBD and healthy controls. During aging, miR-24-3p was identified as a novel candidate biomarker of aging, which could affect the MAPK signaling pathway to increase susceptibility to age-dependent alterations in the immune and inflammatory status, or it could induce apoptosis of salivary glands during aging, decreasing the production of saliva.