Structural insights into fusion mechanisms of small extracellular vesicles with model plasma membranes

Perissinotto, Fabio; Rondelli, Valeria; Senigagliesi, Beatrice; Brocca, Paola; Almásy, László; Bottyán, L.; Merkel, D. G.; Amenitsch, Heinz; Sartori, Barbara; Pachler, Karin; Mayr, Magdalena; Gimona, Mario; Rohde, Eva; Casalis, Loredana; Parisse, Pietro

doi:10.1039/d0nr09075a

Cited by 19 publications

(13 citation statements)

References 68 publications

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“…As emerged by our in-depth analysis, a comprehensive strategy was demonstrated to be effective in discovering new EV classes, 2 , 3 as well as in describing EV-specific internalization mechanisms. 10 , 13 The use of complementary techniques strengthened the understanding on the structural and physicochemical features of the EV-derived supported lipid bilayers, 10 , 11 which are of interest not only for their characterization but also for their beneficial manipulation and exploitation as platforms. The application of structural techniques, 24 linked to molecular profiling, allowed researchers to investigate the direct effect of changes in cells as inhibition of palmitoylation on cell–cell communication by affecting the secreted EV population.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, addressing the mechanisms of fusion and release of cargo is necessary not only to understand but also to mimic and engineer new delivery strategies. Building up on the work done by Gimona’s group on potency assays for mesenchymal stem cell derived EVs, 25 Perissinotto and Rondelli et al 10 applied a set of complementary techniques to unveil new aspects of mesenchymal stem cell derived EV characteristics and internalization mechanisms. After the chemicophysical characteristics of EVs by NTA, cryo-EM, and multiplexed surface marker analysis, a combination of SAXS, SANS, and NR were used to assess the membrane bilayer structure and lipid/protein ratio (by volume) of sEV membranes.…”

Section: Case Studies: From Biophysics To Profiling Integrationmentioning

confidence: 99%

“…Techniques such as light scattering (LS), nanoparticle tracking analysis (NTA), atomic force microscopy (AFM), cryogenic electron microscopy (cryo-EM), scattering and reflectometry of X-rays and neutrons, and vibrational spectroscopies allow the collection of information on the size, structure, mean content, and morphology of EVs, ,,− whereas others such as Western blot analysis, polymerase chain reaction (PCR), next generation sequencing (NGS), and mass spectrometry (MS) allow a comprehensive description of their molecular content − ,,− (see Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Integrated Strategies for a Holistic View of Extracellular Vesicles

et al. 2022

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Extracellular vesicles (EVs) are receiving increasing attention for their role in spreading both beneficial and harmful information during cell–cell communication. The complexity and heterogeneity of the origin of EVs make integrated molecular, structural, and functional studies extremely challenging but necessary at the same time. In fact, a comprehensive interdisciplinary approach is needed to correlate the features of EVs, target cells/organs, and the pathophysiological outcomes exerted by the EVs’ actions. Based on these premises, after introducing a brief state-of-the-art outline on the current analytical approaches exploited to characterize EVs, this review aims to highlight the effectiveness of those studies where authors put in correlation the diverse EV data collected from different points of view. Although these examples are still just a few, they still represent an excellent starting point to be taken as a reference in the perspective for improving the correlation among EV-related clinical aspects. Of course, to fully reach this goal, several points need to be further improved and developed. Undoubtedly, new avenues in diagnostic, prognostic, and therapeutic applications by EVs will be initiated by integrative strategies, combining biophysical approaches, high-throughput omics technologies, and computational models.

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Section: Discussionmentioning

confidence: 99%

Section: Case Studies: From Biophysics To Profiling Integrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated Strategies for a Holistic View of Extracellular Vesicles

et al. 2022

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“…During this process, EVs transfer biologically active cargo to recipient cells, thereby altering the properties of those cells. There are multiple processes by which EVs and their cargo molecules can be transferred to recipient cells, including (i) EVs attaching to the cells and acting as a ligand to activate receptors on the cell surface; (ii) EVs activating a receptor on the surface of the recipient cell without being taken up by the cell, (iii) EVs attaching to the cells and fusing, or (iv) the entire EVs is taken up by endocytosis [ 18 , 19 ]. Once released, the fate of the EVs is based on their size, composition, and the microenvironment.…”

Section: Generation and Properties Of Evs In Pdacmentioning

confidence: 99%

Extracellular vesicle-mediated crosstalk between pancreatic cancer and stromal cells in the tumor microenvironment

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) interacts closely with the tumor microenvironment (TME). The TME is remodeled by crosstalk between pancreatic cancer cells and stromal cells, and is critical for cancer progression. Extracellular vesicles (EVs), including exosomes and microvesicles, help facilitate an exchange of information both within the TME and to distant organs. EVs have also been identified as potential diagnostic biomarkers, therapeutic targets, and drug carriers for pancreatic cancer treatment. Thus, understanding the selective packaging of EVs cargo and its mechanistic impact will increase our understanding of cancer biology. In this review, we collect and analyze recent findings of the pancreatic cancer-stromal cell interactions mediated by EVs and the mechanisms involved in cancer-related immunity and chemoresistance. These studies demonstrate the vital role of EVs in pancreatic cancer reprogramming and TME remodeling. We also summarize the EVs identified as potential PDAC diagnostic biomarkers and possible therapeutic targets. This greater understanding is a promising avenue for transitioning EVs from bench to bedside. Graphical Abstract

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“…Where does the EV fusion occur in target cells? In only a fraction of cases the process occurs at the surface, and cargos are discharged through the plasma membrane ( Figure 3 ) ( Somiya and Kuroda, 2021 ; Perissinotto et al, 2021 ; Song et al, 2021 ; Hung and Leonard, 2016 ). In many other cases fusion, preceded by the internalization of EV in the endocytic system, occurs in a moderately acidic environment ( Figure 3 ) ( Joshi et al, 2020 ; Somiya, 2020 ).…”

Section: Evs: Origin Navigation and Fusion With Target Cellsmentioning

confidence: 99%

Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes

Meldolesi

2022

Front. Cell Dev. Biol.

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In addition to conventional protein secretion, dependent on the specific cleavage of signal sequences, proteins are secreted by other processes, all together called unconventional. Among the mechanisms operative in unconventional secretion, some are based on two families of extracellular vesicle (EVs), expressed by all types of cells: the exosomes (before secretion called ILVs) and ectosomes (average diameters ∼70 and ∼250 nm). The two types of EVs have been largely characterized by extensive studies. ILVs are assembled within endocytic vacuoles by inward budding of small membrane microdomains associated to cytosolic cargos including unconventional secretory proteins. The vacuoles containing ILVs are called multivesicular bodies (MVBs). Upon their possible molecular exchange with autophagosomes, MVBs undergo two alternative forms of fusion: 1. with lysosomes, followed by large digestion of their cargo molecules; and 2. with plasma membrane (called exocytosis), followed by extracellular diffusion of exosomes. The vesicles of the other type, the ectosomes, are differently assembled. Distinct plasma membrane rafts undergo rapid outward budding accompanied by accumulation of cytosolic/secretory cargo molecules, up to their sewing and pinching off. Both types of EV, released to the extracellular fluid in their complete forms including both membrane and cargo, start navigation for various times and distances, until their fusion with target cells. Release/navigation/fusion of EVs establish continuous tridimensional networks exchanging molecules, signals and information among cells. The proteins unconventionally secreted via EVs are a few hundreds. Some of them are functionally relevant (examples FADD, TNF, TACE), governing physiological processes and important diseases. Such proteins, at present intensely investigated, predict future discoveries and innovative developments, relevant for basic research and clinical practice.

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Structural insights into fusion mechanisms of small extracellular vesicles with model plasma membranes

Abstract: Extracellular vesicles (EVs) are a potent intercellular communication system. Such small vesicles transport biomolecules between cells and throughout the body, strongly influencing the fate of recipient cells. Due to their...

Cited by 19 publications

References 68 publications

Integrated Strategies for a Holistic View of Extracellular Vesicles

Integrated Strategies for a Holistic View of Extracellular Vesicles

Extracellular vesicle-mediated crosstalk between pancreatic cancer and stromal cells in the tumor microenvironment

Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes

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