EXOSOMES

Exosomes are released by cells as membrane-bound nanovesicles containing lipids, proteins, nucleic acids, carbohydrates and other metabolites. Exosomes modulate immunity, regeneration, premature aging or inflammation and are ingested by target cells to transfer biological signals between cells. Exosomes are also important as drug carriers, preventative or therapeutic vaccines and biomarkers and are actively being modified for different commercial manufacturing processes (e.g. from cultured human cells or from bovine milk) and are being tested for new uses in Exosome therapeutics and companion diagnostics. MarinBio provides clients with state-of-the-art Exosome services for potential therapeutic, preventative and/or diagnostic research and development.

 

Figure Legend. a. Origin and release of extracellular vesicles includes both MicroVesicles and Exosomes shown above. b. The contents of the Exosomes are shown above. The IntraLumenal Vesicles (ILVs) pinch off the cell membrane. Subsequently, smaller vesicles are formed by the budding inward from the membrane of the IntraLumenal vesicle forming a MultiVesicular Body (MVB). The MultiVesicular Body fuses with the cell membrane expelling the smaller endosomes into the extracellular space as shown in the left panel, adjacent to this legend.

EXOSOMES FUNCTION IN CELL TO CELL OR CELL TO TISSUE COMMUNICATIONS

Exosomes carry markers of the cell of origin and have specialized functions in different physiological processes, including cell proliferation, homeostasis, maturation, antigen presentation, immune responses, intercellular signaling, communication, cell or tissue injury, repair, cellular waste disposition, aging, regeneration and development.

MarinBio provides clients with Exosomes and Exosome bioassays, for example following their release into in vitro normal cell culture growth media, or, for other examples, from tumor cells or stem cells. In short, Exosomes participate in pathological disorders, including inflammation, cancer progression, premature aging, regeneration, wound healing, metabolic disease and cardiovascular disease. Furthermore, Exosomes can carry toxic damaged forms of aggregated proteins that are fated for destruction and are also relevant to the progression of neurodegenerative diseases. MarinBio bioassays are available for clients with pre-clinical R&D or clinical applications of Exosomes or as diagnostic biomarkers and prognostic or therapeutic products.

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Cell-secreted Extracellular Vesicles are important mediators of cell to cell communication in distinct physiological and pathological processes, including cancer. Tumor cells release multiple types of, Extracellular Vesicles, including large Oncosomes, Tumor MicroVesicles, Exosomes of which all based on sizes, morphologies and mechanisms of biogenesis. Tumor MicroVesicles are produced by direct outward budding and fission of the plasma membrane, whereas Exosomes are generated within MultiVesicular Bodies and released through fusion with the plasma membrane. The Extracellular Vesicles selectively package DNAs, RNAs, proteins, lipids, carbohydrates and other metabolites, which are transferred to recipient cells at local and distant microenvironments, for example in promoting tumor progression and metastasis. Knowing the contents of Exosomes, MarinBio and others can improve efficacy by changing what is packaged into them. These modifications are achieved by overexpression of certain proteins or certain RNAs packed within the Exosomes. Also, sequences of DNA or RNA have demonstrated neuroprotective or angiogenic properties when packed inside Exosomes or directed to the Exosomes.

Exosomes may contain various DNA, RNA, proteins, lipids, carbohydrates, and other metabolites of their cell of origin and transfer their contents from one cell to another via membrane vesicle trafficking. For example, Exosomes present proteins/antigens that influence the immune system via Dendritic Cells (DCs), B-cells and via functions in adaptive immune responses to pathogens and/or tumors. DC-derived Exosomes express MHC I antigens, MHC II antigens, co-stimulatory molecules and induce and enhance antigen-specific T-cell responses in vivo. Exosome production and Exosome content is influenced by molecular signals from the cell of origin, for example hypoxic tumor cells secrete Exosomes with enhanced angiogenic and metastatic potential. Exosomes are being tested in cancer immunotherapy and other clinical trials.

Exosomes are the smallest Extracellular Vesicles with sizes between 30 and 150 nm which are generated through the cells’ endolysosomal pathway (as shown in the figure). This pathway begins at the plasma membrane, where the membrane folds inward and then pinches off an empty IntraLuminal Vesicle. The process of endocytosis continues on the membrane of the intraluminal vesicle, creating smaller vesicles commonly known as Exosomes. The empty IntraLuminal Vesicle then matures into a MultiVesicular Body, where the Exosomes accumulate. The MultiVesicular Body can either fuse with the cell’s plasma membrane and release those Exosomes or can further mature into a lysosome. This endolysosomal pathway leading to the generation and release of Exosomes is regulated and the Exosomes encapsulate cell proteins, DNA, RNA and other metabolites.

Exosomes and other Extracellular Vessicles are present in tissues and biological fluids, including blood, urine, cerebrospinal fluid, etc. Exosomes were originally thought to function solely as a mechanism to dispose of unwanted proteins and other molecules, but it is now well established and generally accepted that Exosomes mediate cell to cell communications, for example in immune responses, angiogenesis, proliferation and cell differentiation.

There are three well known Extracellular Vesicles: Exosomes, Apoptotic Bodies and MicroVesicles. which bleb from the cell’s plasma membranes. Apoptotic Bodies are largest with diameters from 800 to 5000 nm. Apoptotic Bodies originate from apoptotic cells and contain fragmented cell nuclei, proteins, DNA, RNA and miRNA. MicroVesicles are smaller in size at between 50 and 1000 nm and bleb from non-apoptotic living cells. Blebbing of MicroVesicles includes trafficking of cellular molecules to the plasma membrane, which results in protrusions from cell’s surfaces, budding and then membrane detachment.

EXOSOMES IN VACCINES AND OTHER THERAPEUTIC PRODUCT DEVELOPMENT

Exosome surface proteins are derived from the plasma membranes of the cells of origin. Exosomes released by Antigen-Presenting Cells (APCs), Dendritic Cells (DCs) and tumor cells are important in vaccine development. Exosomes protect their contents from clearance or damage by either complement fixation or macrophage digestion, due to the Exosome double-layered membrane and nanoscale size, thus prolonging their circulation half-life and improving biological activity. MarinBio is actively working with clients in their Exosome testing and development programs. One example is for FDA requested tests for clients to monitor the potential of Exosomes to modulate (enhance, inhibit, no effect) T-cell mediated immunity in MLR. MarinBio is available for research and development of client exosome-based bioassays for diagnostic/prognostic biomarkers, as well as exosome-based therapeutic product candidates, for example see Figure below.

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