Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes

Trajković, Katarina; Hsu, Chieh; Chiantia, Salvatore; Rajendran, Lawrence; Wenzel, Dirk; Wieland, Felix; Schwille, Petra; Brügger, Britta; Simons, Mikael

doi:10.1126/science.1153124

Cited by 2,838 publications

(2,637 citation statements)

References 25 publications

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“…ESCRT‐III directly participates in remodeling and abscission of the membranes; ultimately, VPS4, the recycling machine, extracts ESCRT‐III monomers from the assembly to recycle the ESCRT‐III subunits 59. An ESCRT‐independent mechanism involves the ceramide‐triggered budding of Exos into MVBs, which is preferentially dependent on certain cargoes 69. Another ESCRT‐independent mechanism involves tetraspanin (for example, CD63)‐mediated organization of particular proteins 70…”

Section: Biogenesis and Release Of Evsmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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Section: Biogenesis and Release Of Evsmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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“…49 In both cases, no liquid phase separation was observed. We do not expect DOPC or DOPC-cholesterol to form these types of structures in the absence of the glycolipid.…”

Section: Resultsmentioning

confidence: 91%

Adding glycolipid functionality to model membranes – phase behaviour of a synthetic glycolipid in a phospholipid membrane

et al. 2014

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Glycolipid phase behaviour is less well understood than for many phospholipids, but due to their structural and functional diversity, glycolipids represent an important group of amphiphiles from which biological function is derived. Here we have incorporated a synthetic glycolipid in binary mixtures with DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) into giant unilamellar vesicles (GUVs) at biologically relevant concentrations and observed the phase behaviour of the lipid mixtures for a range of glycolipid concentrations. At low concentrations, the glycolipid is fully dispersed in the GUV membrane. At glycolipid molar concentrations above 10%, the formation of lipid tubules is observed, and is consistent with the formation of a columnar lipid phase. Lipid tubules are observed in aqueous and oil solvents, suggesting that both hexagonal and inverted hexagonal lipid arrangements can be formed. This work may offer insights into the biological function of glycolipids and the challenges in formulating them for use in industrial applications.

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“…Dynamic light scattering of A1-CM (Figure 2(a), Control A1-CM) revealed abundant EVs within the size range typical for mammalian exosomes and microvesicles (mean diameter: 161.5 nm; modal diameter: 128.6 nm). In mammalian cells, inhibition of the ceramide synthesis pathway using a small molecule inhibitor, GW4869, which targets neutral sphingomyelinase-2 (nSMase2), suppresses exosome secretion [32,33]. A1-EV levels were significantly reduced within the A1-CM in a GW4869 dose-dependent manner (Figure 2(a,b)): at 40 and 100 µM GW4869, two- and fivefold decreases in EV production were observed, respectively.…”

Section: Resultsmentioning

confidence: 99%

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

Middleton

Rogers

Couto

et al. 2018

J of Extracellular Vesicle

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Newts can regenerate amputated limbs and cardiac tissue, unlike mammals which lack broad regenerative capacity. Several signaling pathways involved in cell proliferation, differentiation and survival during newt tissue regeneration have been elucidated, however the factors that coordinate signaling between cells, as well as the conservation of these factors in other animals, are not well defined. Here we report that media conditioned by newt limb explant cells (A1 cells) protect mammalian cardiomyocytes from oxidative stress-induced apoptosis. The cytoprotective effect of A1-conditioned media was negated by exposing A1 cells to GW4869, which suppresses the generation of extracellular vesicles (EVs). A1-EVs are similar in diameter (~100–150 nm), structure, and share several membrane surface and cargo proteins with mammalian exosomes. However, isolated A1-EVs contain significantly higher levels of both RNA and protein per particle than mammalian EVs. Additionally, numerous cargo RNAs and proteins are unique to A1-EVs. Of particular note, A1-EVs contain numerous mRNAs encoding nuclear receptors, membrane ligands, as well as transcription factors. Mammalian cardiomyocytes treated with A1-EVs showed increased expression of genes in the PI3K/AKT pathway, a pivotal player in survival signaling. We conclude that newt cells secrete EVs with diverse, distinctive RNA and protein contents. Despite ~300 million years of evolutionary divergence between newts and mammals, newt EVs confer cytoprotective effects on mammalian cardiomyocytes.

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Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes

Cited by 2,838 publications

References 25 publications

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Adding glycolipid functionality to model membranes – phase behaviour of a synthetic glycolipid in a phospholipid membrane

Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes

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