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      Exosomes: biogenesis, biologic function and clinical potential

      , , ,
      Cell & Bioscience
      Springer Science and Business Media LLC

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          Abstract

          Exosomes are nano-sized biovesicles released into surrounding body fluids upon fusion of multivesicular bodies and the plasma membrane. They were shown to carry cell-specific cargos of proteins, lipids, and genetic materials, and can be selectively taken up by neighboring or distant cells far from their release, reprogramming the recipient cells upon their bioactive compounds. Therefore, the regulated formation of exosomes, specific makeup of their cargo, cell-targeting specificity are of immense biological interest considering extremely high potential of exosomes as non-invasive diagnostic biomarkers, as well as therapeutic nanocarriers. In present review, we outline and discuss recent progress in the elucidation of the regulatory mechanisms of exosome biogenesis, the molecular composition of exosomes, and technologies used in exosome research. Furthermore, we focus on the potential use of exosomes as valuable diagnostic and prognostic biomarkers for their cell-lineage and state-specific contents, and possibilities as therapeutic vehicles for drug and gene delivery. Exosome research is now in its infancy, in-depth understanding of subcellular components and mechanisms involved in exosome formation and specific cell-targeting will bring light on their physiological activities.

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          Most cited references152

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          Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

          Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
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            The future of immune checkpoint therapy.

            Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
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              Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.

              To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
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                Author and article information

                Journal
                Cell & Bioscience
                Cell Biosci
                Springer Science and Business Media LLC
                2045-3701
                December 2019
                February 15 2019
                December 2019
                : 9
                : 1
                Article
                10.1186/s13578-019-0282-2
                144250db-4c8a-4183-85e2-4ffe3b3a65eb
                © 2019

                http://creativecommons.org/licenses/by/4.0/

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