scholarly journals Brain-Derived Extracellular Vesicles are Highly Enriched in the Prion Protein and Its C1 Fragment: Relevance for Cellular Uptake and Implications in Stroke

2019 ◽  
Author(s):  
Santra Brenna ◽  
Hermann C. Altmeppen ◽  
Behnam Mohammadi ◽  
Björn Rissiek ◽  
Florence Schlink ◽  
...  
Keyword(s):  
Prion Protein ◽  
Extracellular Vesicles ◽  
Cellular Uptake ◽  
Intercellular Communication ◽  
Cell Types ◽  
Brain Cell ◽  
Surface Proteins ◽  
Therapeutic Interventions ◽  
Ischemic Region ◽  
Brain Artery

ABSTRACTExtracellular vesicles (EVs) are important means of intercellular communication and a potent tool for regenerative therapy. In ischemic stroke, transient blockage of a brain artery leads to a lack of glucose and oxygen in the affected brain tissue, provoking neuronal death by necrosis in the core of the ischemic region. The fate of neurons in the surrounding penumbra depends on the stimuli, including EVs, received during the following hours. A detailed characterization of such stimuli is crucial not only for understanding stroke pathophysiology but also for new therapeutic interventions.In the present study, we characterize the EVs in mouse brain under physiological conditions and 24h after induction of transient ischemia in mice. We show that, in steady-state conditions, microglia are the main source of small EVs (sEVs) whereas after ischemia, the main EV population originates from astrocytes. Moreover, sEVs presented high amounts of the prion protein (PrP) which were increased after stroke. Conspicuously, sEVs were particularly enriched in a truncated PrP fragment (PrP-C1). Because of similarities between PrP-C1 and certain viral surface proteins, we studied the cellular uptake of brain-derived sEVs from mice lacking (PrP-KO) or containing PrP (WT). We show that PrP-KO-EVs are rapidly taken up by neurons and colocalize with lysosomes. Although eventually WT-EVs are also found in lysosomes, the amount taken up by neurons is significantly higher for PrP-KO-EVs. Likewise, microglia and astrocytes were also engulfing PrP-KO-sEVs more efficiently than WT-sEVs.Our results provide information on the relative contribution of brain cell types to the sEV pool in mice and indicate that increased release of sEVs by astrocytes together with elevated levels of PrP in sEVs may play a role in intercellular communication at early stages after stroke. In addition, amounts of PrP (and probably PrP-C1) in brain sEVs seem to contribute to their cellular uptake.

scholarly journals LAMP2A regulates the loading of proteins into exosomes.

2021 ◽  
Author(s):  
Joao Vasco Ferreira ◽  
Ana da Rosa Soares ◽  
Jose S. Ramalho ◽  
Catarina Maximo Carvalho ◽  
Maria Helena Cardoso ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Membrane Protein ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Fluorescent Proteins ◽  
Cell Types ◽  
Zebrafish Larvae ◽  
Escrt Machinery ◽  
Bioactive Proteins ◽  
Exosome Biogenesis

Exosomes are extracellular vesicles of endosomal origin released by virtually all cell types across metazoans. Exosomes are active vehicles of intercellular communication and can transfer lipids, RNAs and proteins between different cells, tissues or organs. However, the mechanisms that regulate the selective loading of cytosolic proteins into these vesicles are still largely unknow. Here we describe a mechanism whereby proteins containing a pentapeptide sequence, biochemically related to the KFERQ-motif, are loaded into a subpopulation of exosomes in a process that is dependent on the membrane protein LAMP2A. Moreover, this mechanism is independent of the ESCRT machinery components TSG101 and VPS4b and dependent on HSC70, CD63, Alix, Syntenin-1, Rab31 and ceramides. The transcription factor and master regulator of hypoxia HIF1A is loaded into exosomes by this mechanism to transport hypoxia signaling to normoxic cells. Additionally, by tagging fluorescent proteins with KFERQ-like sequences we were able to follow inter-organ transfer of exosomes in zebrafish larvae. Our findings identify LAMP2A as a key component in exosome biogenesis while opening new avenues for exosome engineering by allowing the loading of bioactive proteins by tagging them with KFERQ-like motifs.

scholarly journals Emerging roles of extracellular vesicles in the intercellular communication for exercise-induced adaptations

2020 ◽  
Vol 319 (2) ◽  
pp. E320-E329
Author(s):  
Joshua Denham ◽  
Sarah J. Spencer
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Biological Material ◽  
Molecular Mechanisms ◽  
Health Benefits ◽  
Extracellular Vesicle ◽  
Therapeutic Interventions ◽  
Current Evidence ◽  
Future Research ◽  
Age Related

Complex organisms rely heavily on intercellular communication. The rapidly expanding field of extracellular vesicle biology has made it clear that the necessary intercellular communication occurs partly through their paracrine and endocrine actions. Extracellular vesicles are nanoscale lipid membranes (30–2,000 nm in diameter) that shuttle functional biological material between cells. They are released from numerous tissues and are isolated from nearly all biofluids and cell cultures. Although their biogenesis, cell targeting, and functional roles are incompletely understood, they appear to have crucial roles in physiological and disease processes. Their enormous potential to serve as sensitive biomarkers of disease and also new therapeutic interventions for diseases have gained them considerable attention in recent years. Regular physical exercise training confers systemic health benefits and consequently prevents many age-related degenerative diseases. Many of the molecular mechanisms responsible for the salubrious effects of exercise are known, yet a common underlying mechanism potentially responsible for the holistic health benefits of exercise has only recently been explored (i.e., via extracellular vesicle transport of biological material). Here, we provide an overview of extracellular vesicle biology before outlining the current evidence on the capacity for a single bout and chronic exercise to elicit changes in extracellular vesicle content and modulate their molecular cargo (e.g., small RNAs). We highlight areas for future research and emphasize their potential utility as biomarkers and therapeutic strategies of disease and its prevention.

scholarly journals The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1964
Author(s):  
Anjali Balakrishnan ◽  
Sabrina Roy ◽  
Taylor Fleming ◽  
Hon S. Leong ◽  
Carol Schuurmans
Keyword(s):  
Tumor Progression ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Cell Types ◽  
Disease Diagnosis ◽  
Neural Cells ◽  
Cell Of Origin ◽  
Cell Type Specificity ◽  
Normal Cells ◽  
Mediate Cell

Gliomas are a diverse group of brain tumors comprised of malignant cells (‘tumor’ cells) and non-malignant ‘normal’ cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both ‘tumor’ and ‘normal’ cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell–cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that ‘vesiculome’ data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.

scholarly journals Connexin-46 Contained in Extracellular Vesicles Enhance Malignancy Features in Breast Cancer Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 676 ◽  
Author(s):  
Rodrigo A. Acuña ◽  
Manuel Varas-Godoy ◽  
Viviana M. Berthoud ◽  
Ivan E. Alfaro ◽  
Mauricio A. Retamal
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Breast Cancer Cells ◽  
Recipient Cell ◽  
Cell Types ◽  
Migration And Invasion ◽  
Long Distance ◽  
Cancer Aggressiveness

Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six subunits of transmembrane proteins called connexins (Cx). For many years, it was believed that the loss of GJC-mediated intercellular communication was a hallmark in cancer development. However, nowadays this paradigm is changing. The connexin 46 (Cx46), which is almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and is correlated with tumor growth in a Xenograft mouse model. On the other hand, extracellular vesicles (EVs) have an important role in long-distance communication under physiological conditions. In the last decade, EVs also have been recognized as key players in cancer aggressiveness. The aim of this work was to explore the involvement of Cx46 in EV-mediated intercellular communication. Here, we demonstrated for the first time, that Cx46 is contained in EVs released from breast cancer cells overexpressing Cx46 (EVs-Cx46). This EV-Cx46 facilitates the interaction between EVs and the recipient cell resulting in an increase in their migration and invasion properties. Our results suggest that EV-Cx46 could be a marker of cancer malignancy and open the possibility to consider Cx46 as a new therapeutic target in cancer treatment.

scholarly journals Apoptotic Bodies: Particular Extracellular Vesicles Involved in Intercellular Communication

Biology ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 21 ◽  
Author(s):  
Michela Battistelli ◽  
Elisabetta Falcieri
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Genetic Information ◽  
Cell Communication ◽  
Cell Types ◽  
Apoptotic Bodies ◽  
Species Barrier ◽  
Physiological Conditions ◽  
Different Types ◽  
Different Cell Types

In the last decade, a new method of cell–cell communication mediated by membranous extracellular vesicles (EVs) has emerged. EVs, including exosomes, microvesicles, and apoptotic bodies (ApoBDs), represent a new and important topic, because they are a means of communication between cells and they can also be involved in removing cellular contents. EVs are characterized by differences in size, origin, and content and different types have different functions. They appear as membranous sacs released by a variety of cells, in different physiological and patho-physiological conditions. Intringuingly, exosomes and microvesicles are a potent source of genetic information carriers between different cell types both within a species and even across a species barrier. New, and therefore still relatively poorly known vesicles are apoptotic bodies, on which numerous in-depth studies are needed in order to understand their role and possible function. In this review we would like to analyze their morpho-functional characteristics.

scholarly journals Extracellular Vesicles in Skin Wound Healing

2021 ◽  
Author(s):  
Deimantė Narauskaitė ◽  
Gabrielė Vydmantaitė ◽  
Justina Rusteikaitė ◽  
Revathi Sampath ◽  
Akvilė Rudaitytė ◽  
...  
Keyword(s):  
Wound Healing ◽  
Extracellular Vesicles ◽  
Current Knowledge ◽  
Skin Wound ◽  
Surface Proteins ◽  
Therapeutic Interventions ◽  
Skin Wound Healing ◽  
Skin Repair ◽  
Healing Wound ◽  
Healing Phase

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, EV-based signalling takes part in all four wound healing phases: hemostasis, inflammation, proliferation and remodelling. Such an extensive involvement of EVs suggests exploiting their action to modulate the impaired healing phase. Furthermore, next to their natural wound healing capacity, EVs can be engineered for better defined pharmaceutical purposes, such as carrying specific cargo or targeting specific destinations by labelling them with certain surface proteins. This review aims to promote scientific awareness in basic and translational research of EVs by summarizing the current knowledge about their natural role in each stage of skin repair and the most recent findings in application areas, such as wound healing, skin regeneration and treatment of dermal diseases, including the stem cell-derived, plant-derived and engineered EVs.

scholarly journals Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 957
Author(s):  
Cristina Mas-Bargues ◽  
Jorge Sanz-Ros ◽  
Aurora Román-Domínguez ◽  
Lucia Gimeno-Mallench ◽  
Marta Inglés ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Cell Function ◽  
Cell Types ◽  
Culture Conditions ◽  
Target Cells ◽  
Activity Levels ◽  
Functional Changes

Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current stem cell-based therapies. Extracellular vesicles (EVs) contain a cell-specific cargo of proteins, lipids and nucleic acids that are released and taken up by probably all cell types, thereby inducing functional changes via the horizontal transfer of their cargo. Here, we describe the beneficial properties of extracellular vesicles derived from non-senescent MSC, cultured in a low physiological oxygen tension (3%) microenvironment into prematurely senescent MSC, cultured in a hyperoxic ambient (usual oxygen culture conditions, i.e., 21%). We observed that senescent MCS, treated with EVs from non-senescent MCS, showed reduced SA-β-galactosidase activity levels and pluripotency factor (OCT4, SOX2, KLF4 and cMYC, or OSKM) overexpression and increased glycolysis, as well as reduced oxidative phosphorylation (OXPHOS). Moreover, these EVs’ cargo induced the upregulation of miR-302b and HIF-1α levels in the target cells. We propose that miR-302b triggered HIF-1α upregulation, which in turn activated different pathways to delay premature senescence, improve stemness and switch energetic metabolism towards glycolysis. Taken together, we suggest that EVs could be a powerful tool to restore altered intercellular communication and improve stem cell function and stemness, thus delaying stem cell exhaustion in aging.

scholarly journals Extracellular Vesicles in Skin Wound Healing

2021 ◽  
Vol 14 (8) ◽  
pp. 811
Author(s):  
Deimantė Narauskaitė ◽  
Gabrielė Vydmantaitė ◽  
Justina Rusteikaitė ◽  
Revathi Sampath ◽  
Akvilė Rudaitytė ◽  
...  
Keyword(s):  
Wound Healing ◽  
Extracellular Vesicles ◽  
Current Knowledge ◽  
Skin Wound ◽  
Surface Proteins ◽  
Therapeutic Interventions ◽  
Skin Wound Healing ◽  
Skin Repair ◽  
Healing Wound ◽  
Healing Phase

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, EV-based signaling takes part in all four wound healing phases: hemostasis, inflammation, proliferation, and remodeling. Such an extensive involvement of EVs suggests exploiting their action to modulate the impaired healing phase. Furthermore, next to their natural wound healing capacity, EVs can be engineered for better defined pharmaceutical purposes, such as carrying specific cargo or targeting specific destinations by labelling them with certain surface proteins. This review aims to promote scientific awareness in basic and translational research of EVs by summarizing the current knowledge about their natural role in each stage of skin repair and the most recent findings in application areas, such as wound healing, skin regeneration, and treatment of dermal diseases, including the stem cell-derived, plant-derived, and engineered EVs.

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