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Journal ArticleDOI: 10.1080/14712598.2021.1825677

Small extracellular vesicles (sEVs): discovery, functions, applications, detection methods and various engineered forms.

04 Mar 2021-Expert Opinion on Biological Therapy (Informa UK Limited)-Vol. 21, Iss: 3, pp 1-24
Abstract: Extracellular vesicles (EVs) are cell-created delivery systems of proteins, lipids, or nucleic acids, and means of extracellular communication. Though sEVs were initially considered to be the waste...

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12 results found


Open accessJournal Article
Shun-ichi Nakamura1, T. Kajimoto1, Taro Okada1, S. Miya1  +1 moreInstitutions (1)
Abstract: During late endosome maturation, cargo molecules are sorted into intralumenal vesicles (ILVs) of multivesicular endosomes (MVEs), and are either delivered to lysosomes for degradation or fused with the plasma membranes for exosome release. The mechanism underlying formation of exosomal ILVs and cargo sorting into ILVs destined for exosome release is still unclear. Here we show that inhibitory G protein (Gi)-coupled sphingosine 1-phosphate (S1P) receptors regulate exosomal MVE maturation. Gi-coupled S1P receptors on MVEs are constitutively activated through a constant supply of S1P via autocrine activation within organelles. We also found that the continuous activation of Gi-coupled S1P receptors on MVEs is essential for cargo sorting into ILVs destined for exosome release. Our results reveal a mechanism underlying ESCRT-independent maturation of exosomal MVEs.

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Topics: Sphingosine-1-phosphate (56%), Endosome (55%)

154 Citations


Open accessJournal Article
Abstract: Background/Aims: To evaluate whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model. Methods: For the in vitro study, a Cell Counting Kit-8 (CCK-8) array and proteomic analysis were performed. For the in vivo study, female rats were divided into four groups: sham, SUI, adipose-derived stem cell (ADSC), and exosomes (n = 12 each). The SUI model was generated by pudendal nerve transection and vaginal dilation. Vehicle, hADSCs, or exosomes were injected into the peripheral urethra. After 2, 4, and 8 weeks, the rats underwent cystometrography and leak point pressure (LPP) testing, and tissues were harvested for histochemical analyses. Results: The CCK-8 experiment demonstrated that ADSC-derived exosomes could enhance the growth of skeletal muscle and Schwann cell lines in a dose-dependent manner. Proteomic analysis revealed that ADSC-derived exosomes contained various proteins of different signaling pathways. Some of these proteins are associated with the PI3K-Akt, Jak-STAT, and Wnt pathways, which are related to skeletal muscle and nerve regeneration and proliferation. In vivo experiments illustrated that rats of the exosome group had higher bladder capacity and LPP, and had more striated muscle fibers and peripheral nerve fibers in the urethra than rats of the SUI group. Both urethral function and histology of rats in the exosome group were slightly better than those in the ADSC group. Conclusions: Local injection of hADSC-derived exosomes improved functional and histological recovery after SUI.

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Topics: Adipose tissue (55%), Urinary incontinence (52%), In vivo (51%)

16 Citations


Journal ArticleDOI: 10.1007/S00604-021-04790-5
Shiana Malhotra1, Zarinah M Amin1, Garima Dobhal1, Sophie Cottam1  +2 moreInstitutions (1)
26 Mar 2021-Mikrochimica Acta
Abstract: Extracellular vesicles are spherical nanoparticles inherently released by almost all cell types. They acquire the cell's membrane and cytoplasmic characteristics offering abundant identical units that can be captured to recognize the cell of origin. The abundance of vital cell information and multifunctional roles in cellular processes has rendered them attention, particularly as promising biomarkers for disease diagnosis and use in potential drug delivery systems. This review provides insights into standard approaches towards cultivation and isolation of mammalian and bacterial extracellular vesicles. We assess gaps in conventional separation and detection technologies while also tracking developments in ongoing research. The review focuses on highlighting alternative state-of-the-art microfluidic devices that offer avenues for fast, cost-effective, precision-oriented capture and sensing of extracellular vesicles. Combining different detection technologies on an integrated "lab-on-a-chip" system has the prospective to provide customizable opportunities for clinical use of extracellular vesicles in disease diagnostics and therapeutic applications.

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2 Citations


Journal ArticleDOI: 10.1016/J.LFS.2021.119937
15 Nov 2021-Life Sciences
Abstract: Background Secreted microRNAs (miRNAs) can serve as promising diagnostic markers for colorectal cancer (CRC). Herein, we evaluated the potential clinical significance of a signature of four circulating serum-derived miRNAs in CRC. We also demonstrated that extracellular vesicles (EVs) containing miR-221-3p could facilitate endothelial cell angiogenesis. Methods The expressions of four circulating serum-derived miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) were measured by real-time quantitative PCR, and their associations with lymph node metastasis were determined in CRC patients. Receiver operating characteristic curve analysis was used to determine their diagnostic accuracy. EVs were isolated and characterized from the conditioned media of human CRC cells (HCT116 and Caco2). Cell proliferation, transwell migration, and tube formation assays were performed to investigate the pro-angiogenic effect of miR-221-3p transferred by CRC-EVs into the endothelial cells. In silico analysis was used to show the regulatory functions of miR-221-3p on SOCS3, validated by luciferase and Western blotting assays. Results The expression levels of serum-derived miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p were significantly higher in CRC than in healthy individuals. The expression of miR-19a-3p, miR-203-3p, and miR-221-3p were positively correlated with the lymph node metastasis status. Moreover, SOCS3 was identified as a direct target of miR-221-3p and the secreted miR-221-3p shuttled by CRC-EVs regulated STAT3/VEGFR-2 signaling axis by targeting SOCS3 in endothelial cells. CRC-EVs promoted endothelial cell proliferation, migration, and the formation of vessel-like structures. The proangiogenic effect of CRC-EVs on the cells was recapitulated by miR-221-3p overexpression, showing the importance of EVs-derived miR-221-3p in promoting endothelial cell angiogenesis. Conclusion We introduced a signature of four-circulating miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) as a novel diagnostic biomarker for CRC. Besides, we revealed that miR-221-3p induces endothelial cell angiogenesis in vitro by targeting SOCS3.

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Topics: Angiogenesis (65%), Endothelial stem cell (55%), Cell growth (53%) ... read more

1 Citations


Journal ArticleDOI: 10.1016/J.COCIS.2021.101460
Anne des Rieux1Institutions (1)
Abstract: One of the most explored strategies to cure neurological disorders is the transplantation of stem cells and their derived products. Different stem cells, as well as their extracellular vesicles (EV), modified or not, have been administrated in a large array of preclinical neurological disorder models. EV represent the hope of a “cell-free” therapy that would combine the therapeutic potential of stem cells without their drawbacks. Stem cells and EV showed various degrees of efficiency but, overall, provided benefits and improvements. The administration route has a considerable impact on stem cell and EV safety and therapeutic effect. However, despite evidences of preclinical success, the different strategies developed based on stem cells to treat neurological disorders do not exactly recapitulate in clinical trials. Discrepancies between preclinical and clinical experimental conditions and settings, cell availability and difficulties to scale up and to produce cells and EV in a Good Manufacturing Practices (GMP) environment limit translation.

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Topics: Stem cell (60%), Transplantation (52%)

References
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254 results found


Journal ArticleDOI: 10.1038/NCB1596
Abstract: 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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Topics: Exosome (69%), RNA silencing (61%), RNA (60%) ... read more

8,887 Citations


Journal ArticleDOI: 10.1038/NRI855
Abstract: Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture. Interest in exosomes has intensified after their recent description in antigen-presenting cells and the observation that they can stimulate immune responses in vivo. In the past few years, several groups have reported the secretion of exosomes by various cell types, and have discussed their potential biological functions. Here, we describe the physical properties that define exosomes as a specific population of secreted vesicles, we summarize their biological effects, particularly on the immune system, and we discuss the potential roles that secreted vesicles could have as intercellular messengers.

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Topics: Exosome (70%), Microvesicles (56%), Circulating microvesicle (55%)

3,703 Citations


Open accessJournal ArticleDOI: 10.1002/0471143030.CB0322S30
Abstract: Exosomes are small membrane vesicles found in cell culture supernatants and in different biological fluids. Exosomes form in a particular population of endosomes, called multivesicular bodies (MVBs), by inward budding into the lumen of the compartment. Upon fusion of MVBs with the plasma membrane, these internal vesicles are secreted. Exosomes possess a defined set of membrane and cytosolic proteins. The physiological function of exosomes is still a matter of debate, but increasing results in various experimental systems suggest their involvement in multiple biological processes. Because both cell-culture supernatants and biological fluids contain different types of lipid membranes, it is critical to perform high-quality exosome purification. This unit describes different approaches for exosome purification from various sources, and discusses methods to evaluate the purity and homogeneity of the purified exosome preparations.

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Topics: Exosome (69%), Exosomal secretion (52%), Circulating microvesicle (52%) ... read more

3,640 Citations


Open accessJournal ArticleDOI: 10.1080/20013078.2018.1535750
Clotilde Théry1, Kenneth W. Witwer2, Elena Aikawa3, María José Alcaraz4  +414 moreInstitutions (209)
Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

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Topics: Extracellular vesicle (56%)

3,093 Citations


Open accessJournal ArticleDOI: 10.1084/JEM.183.3.1161
Graça Raposo1, Hans W. Nijman1, Willem Stoorvogel1, R Liejendekker1  +3 moreInstitutions (1)
Abstract: Antigen-presenting cells contain a specialized late endocytic compartment, MIIC (major histocompatibility complex [MHC] class II-enriched compartment), that harbors newly synthesized MHC class II molecules in transit to the plasma membrane. MIICs have a limiting membrane enclosing characteristic internal membrane vesicles. Both the limiting membrane and the internal vesicles contain MHC class II. In this study on B lymphoblastoid cells, we demonstrate by immunoelectron microscopy that the limiting membrane of MIICs can fuse directly with the plasma membrane, resulting in release from the cells of internal MHC class II-containing vesicles. These secreted vesicles, named exosomes, were isolated from the cell culture media by differential centrifugation followed by flotation on sucrose density gradients. The overall surface protein composition of exosomes differed significantly from that of the plasma membrane. Exosome-bound MHC class II was in a compact, peptide-bound conformation. Metabolically labeled MHC class II was released into the extracellular medium with relatively slow kinetics, 10 +/- 4% in 24 h, indicating that direct fusion of MIICs with the plasma membrane is not the major pathway by which MHC class II reaches the plasma membrane. Exosomes derived from both human and murine B lymphocytes induced antigen-specific MHC class II-restricted T cell responses. These data suggest a role for exosomes in antigen presentation in vivo.

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Topics: MHC class I (63%), Antigen processing (63%), MHC class II (59%) ... read more

2,576 Citations