A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes

Abstract

Exosomes are nanoscale-sized membrane vesicles secreted by almost all cell types into the extracellular environment upon fusion of multivesicular bodies and plasma membrane. Biogenesis of exosomes is a protein quality control mechanism, and once released, exosomes transmit signals to other cells. The applications of exosomes have increased immensely in biomedical fields owing to their cell-specific cargos that facilitate intercellular communications with neighboring cells through the transfer of biologically active compounds. The diverse constituents of exosomes reflect their cell of origin and their detection in biological fluids represents a diagnostic marker for various diseases. Exosome research is expanding rapidly due to the potential for clinical application to therapeutics and diagnosis. However, several aspects of exosome biology remain elusive. To discover the use of exosomes in the biomedical applications, we must better understand the basic molecular mechanisms underlying their biogenesis and function. In this comprehensive review, we describe factors involved in exosomes biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. In addition, we discuss the role of exosomes as diagnostic markers, and their therapeutic and clinical implications. Furthermore, we addressed the challenges and outstanding developments in exosome research, and discuss future perspectives.

Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: From 1946 to Today

“…This technique was used broadly, alone or along with EM and other techniques, to study the properties, biological content, and identification markers of these smallest EVs, the exosomes. Extensive literature has revealed how exosomes can be identified by the expression of endosome tetraspanins (CD37, CD53, CD63, CD81, and CD82, among others), which are possibly responsible for cell penetration, invasion and fusion events [50,51]. Furthermore, in 2007 Valadi et al [52] showed that exosomes obtained from human mast cell line cultures, identified by ultracentrifugation and expression of CD63 by FACS analysis, contained RNA from approximately 1000 genes, many of which were not present in the cytoplasm of the donor cell.…”

“…Exosomes are different. It is well accepted that the "real" exosomes [51] are small EVs, which are formed by a process of inward budding in early endosomes, later forming multivesicular endosomes and eventually multivesicular bodies (MVBs) (Figure 3), which after fusion with the cell membrane release exosomes into the extracellular microenvironment to transfer their components [39,57].…”

Tumor-derived exosomal components: the multifaceted roles and mechanisms in breast cancer metastasis

“…In addition to the above extrinsic biological factors, it is important that exosome biogenesis and uptake are also influenced by several external factors, such as cell type, cell state, hypoxia, serum conditions, the added cytokines and growth factors and even the separation and purification method of exosomes 35 . Targeting the biogenesis, release and uptake of exosomes might be a potential therapeutic approach to change the course of cancer.…”

The Cellular and Biological Impact of Extracellular Vesicles in Pancreatic Cancer

“…Besides the complexity of the transmitted message, EVs-mediated crosstalk is further regulated by their mode of action or internalization in recipient cells, including macropinocytosis, receptor-mediated endocytosis, phagocytosis or receptor-mediated signaling, which influences the ultimate fate of the transmitted information [ 10 ]. EVs are now reported as major actors of cellular crosstalk in physiological and physio-pathological contexts involving adaptive and responsive processes [ 11 ], which suggests that EVs’ production, secretion and uptake are part of a larger network of communication.…”