Extracellular Vesicles: Potential Mediators of Psychosocial Stress Contribution to Osteoporosis?

Osteoporosis is characterized by low bone mass and damage to the bone tissue’s microarchitecture, leading to increased fracture risk. Several studies have provided evidence for associations between psychosocial stress and osteoporosis through various pathways, including the hypothalamic-pituitary-adrenocortical axis, the sympathetic nervous system, and other endocrine factors. As psychosocial stress provokes oxidative cellular stress with consequences for mitochondrial function and cell signaling (e.g., gene expression, inflammation), it is of interest whether extracellular vesicles (EVs) may be a relevant biomarker in this context or act by transporting substances. EVs are intercellular communicators, transfer substances encapsulated in them, modify the phenotype and function of target cells, mediate cell-cell communication, and, therefore, have critical applications in disease progression and clinical diagnosis and therapy. This review summarizes the characteristics of EVs, their role in stress and osteoporosis, and their benefit as biological markers. We demonstrate that EVs are potential mediators of psychosocial stress and osteoporosis and may be beneficial in innovative research settings.

Download Full-text

The Aquatic Invertebrate Hydra vulgaris Releases Molecular Messages Through Extracellular Vesicles

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.788117 ◽

2021 ◽

Vol 9 ◽

Author(s):

Maria Moros ◽

Eugenio Fergola ◽

Valentina Marchesano ◽

Margherita Mutarelli ◽

Giuseppina Tommasini ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Population Level ◽

Target Cells ◽

Chemical Information ◽

Hydra Vulgaris ◽

Physiological Processes ◽

Developmental Signalling ◽

And Function ◽

Cell Cell

Recent body of evidence demonstrates that extracellular vesicles (EVs) represent the first language of cell-cell communication emerged during evolution. In aquatic environments, transferring signals between cells by EVs offers protection against degradation, allowing delivering of chemical information in high local concentrations to the target cells. The packaging of multiple signals, including those of hydrophobic nature, ensures target cells to receive the same EV-conveyed messages, and the coordination of a variety of physiological processes across cells of a single organisms, or at the population level, i.e., mediating the population’s response to changing environmental conditions. Here, we purified EVs from the medium of the freshwater invertebrate Hydra vulgaris, and the molecular profiling by proteomic and transcriptomic analyses revealed multiple markers of the exosome EV subtype, from structural proteins to stress induced messages promoting cell survival. Moreover, positive and negative regulators of the Wnt/β-catenin signaling pathway, the major developmental pathway acting in body axial patterning, were identified. Functional analysis on amputated polyps revealed EV ability to modulate both head and foot regeneration, suggesting bioactivity of the EV cargo and opening new perspectives on the mechanisms of developmental signalling. Our results open the path to unravel EV biogenesis and function in all cnidarian species, tracing back the origin of the cell-cell, cross-species or cross-kingdom communication in aquatic ecosystems.

Download Full-text

Tracing back the origin of cell-cell communication: Hydra vulgaris releases extracellular vesicles delivering regulators of head and foot regeneration

10.21203/rs.3.rs-763240/v1 ◽

2021 ◽

Author(s):

Maria Moros ◽

Eugenio Fergola ◽

Valentina Marchesano ◽

Margherita Mutarelli ◽

Giuseppina Tommasini ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Population Level ◽

Active Role ◽

Target Cells ◽

Chemical Information ◽

Long Distance ◽

Hydra Vulgaris ◽

And Function ◽

Cell Cell

Abstract Recent body of evidence demonstrates that extracellular vesicles (EVs) represent the first language of cell-cell communication emerged during evolution. In aquatic environments, transferring signals between cells by EVs offer protection against degradation, allowing delivering of chemical information in high local concentrations to the target cells. The packaging of multiple signals, including those of hydrophobic nature, ensures target cells to receive the same EV-conveyed messages, and the coordination of a variety of physiological processes across cells of a single organisms, or at the population level, i.e. mediating the population´s response to changing environmental conditions. Here, we purified EVs from the medium of the freshwater invertebrate Hydra vulgaris, and the molecular profiling by proteomic and transcriptomic analyses revealed multiple markers of the exosome EV subtype. Moreover, positive and negative regulators of the Wnt/β-catenin signaling pathway, the major developmental pathway acting in body axial patterning, were identified. Functional analysis on amputated polyps revealed EV ability to interfere with both head and foot regeneration, suggesting an active role in setting up tissue gradients and oro-aboral polarity through delivery of short and long-distance signals. Our results open the path to unravel EV biogenesis and function in all cnidarian species, tracing back the origin of the cell-cell, cross-species or cross-kingdom communication in aquatic ecosystems

Download Full-text

Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: From 1946 to Today

International Journal of Molecular Sciences ◽

10.3390/ijms22126417 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6417

Author(s):

Erica Bazzan ◽

Mariaenrica Tinè ◽

Alvise Casara ◽

Davide Biondini ◽

Umberto Semenzato ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Phospholipid Bilayers ◽

Cell Of Origin ◽

Therapeutic Tool ◽

Scientific Publications ◽

Cell Processes ◽

Mediate Cell ◽

Definition Of ◽

And Function

Extracellular vesicles (EVs) are a family of particles/vesicles present in blood and body fluids, composed of phospholipid bilayers that carry a variety of molecules that can mediate cell communication, modulating crucial cell processes such as homeostasis, induction/dampening of inflammation, and promotion of repair. Their existence, initially suspected in 1946 and confirmed in 1967, spurred a sharp increase in the number of scientific publications. Paradoxically, the increasing interest for EV content and function progressively reduced the relevance for a precise nomenclature in classifying EVs, therefore leading to a confusing scientific production. The aim of this review was to analyze the evolution of the progress in the knowledge and definition of EVs over the years, with an overview of the methodologies used for the identification of the vesicles, their cell of origin, and the detection of their cargo. The MISEV 2018 guidelines for the proper recognition nomenclature and ways to study EVs are summarized. The review finishes with a “more questions than answers” chapter, in which some of the problems we still face to fully understand the EV function and potential as a diagnostic and therapeutic tool are analyzed.

Download Full-text

Cell-to-Cell Communication by Host-Released Extracellular Vesicles in the Gut: Implications in Health and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22042213 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2213

Author(s):

Natalia Diaz-Garrido ◽

Cecilia Cordero ◽

Yenifer Olivo-Martinez ◽

Josefa Badia ◽

Laura Baldomà

Keyword(s):

Extracellular Vesicles ◽

Intestinal Mucosa ◽

Current Knowledge ◽

Cell Communication ◽

Bioactive Molecules ◽

Target Cells ◽

Immune Functions ◽

Intestinal Homeostasis ◽

General Terms ◽

Health And Disease

Communication between cells is crucial to preserve body homeostasis and health. Tightly controlled intercellular dialog is particularly relevant in the gut, where cells of the intestinal mucosa are constantly exposed to millions of microbes that have great impact on intestinal homeostasis by controlling barrier and immune functions. Recent knowledge involves extracellular vesicles (EVs) as mediators of such communication by transferring messenger bioactive molecules including proteins, lipids, and miRNAs between cells and tissues. The specific functions of EVs principally depend on the internal cargo, which upon delivery to target cells trigger signal events that modulate cellular functions. The vesicular cargo is greatly influenced by genetic, pathological, and environmental factors. This finding provides the basis for investigating potential clinical applications of EVs as therapeutic targets or diagnostic biomarkers. Here, we review current knowledge on the biogenesis and cargo composition of EVs in general terms. We then focus the attention to EVs released by cells of the intestinal mucosa and their impact on intestinal homeostasis in health and disease. We specifically highlight their role on epithelial barrier integrity, wound healing of epithelial cells, immunity, and microbiota shaping. Microbiota-derived EVs are not reviewed here.

Download Full-text

Extracellular vesicles (exosomes and ectosomes) play key roles in the pathology of brain diseases

Molecular Biomedicine ◽

10.1186/s43556-021-00040-5 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Jacopo Meldolesi

Keyword(s):

Multiple Sclerosis ◽

Extracellular Vesicles ◽

Brain Diseases ◽

Target Cells ◽

Surface Binding ◽

Cells Of Origin ◽

Relapsing Remitting ◽

And Function ◽

The Brain

AbstractLast century, neurons and glial cells were mostly believed to play distinct functions, relevant for the brain. Progressively, however, it became clear that neurons, astrocytes and microglia co-operate intensely with each other by release/binding of signaling factors, direct surface binding and generation/release of extracellular vesicles, the exosomes and ectosomes, called together vesicles in this abstract. The present review is focused on these vesicles, fundamental in various brain diseases. Their properties are extraordinary. The specificity of their membrane governs their fusion with distinct target cells, variable depending on the state and specificity of their cells of origin and target. Result of vesicle fusion is the discharge of their cargos into the cytoplasm of target cells. Cargos are composed of critical molecules, from proteins (various nature and function) to nucleotides (especially miRNAs), playing critical roles in immune and neurodegenerative diseases. Among immune diseases is multiple sclerosis, affected by extensive dysregulation of co-trafficking neural and glial vesicles, with distinct miRNAs inducing severe or reducing effects. The vesicle-dependent differences between progressive and relapsing-remitting forms of the disease are relevant for clinical developments. In Alzheimer’s disease the vesicles can affect the brain by changing their generation and inducing co-release of effective proteins, such Aβ and tau, from neurons and astrocytes. Specific miRNAs can delay the long-term development of the disease. Upon their traffic through the blood-brainbarrier, vesicles of various origin reach fluids where they are essential for the identification of biomarkers, important for diagnostic and therapeutic innovations, critical for the future of many brain patients.

Download Full-text

Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C

Frontiers in Immunology ◽

10.3389/fimmu.2021.671485 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lucas Albacete-Albacete ◽

Miguel Sánchez-Álvarez ◽

Miguel Angel del Pozo

Keyword(s):

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Cell Communication ◽

Cell Types ◽

Target Cells ◽

Tenascin C ◽

Signalling Molecules ◽

Inflammatory Processes ◽

Bona Fide ◽

Cellular Components

ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.

Download Full-text

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

International Journal of Molecular Sciences ◽

10.3390/ijms21010266 ◽

2019 ◽

Vol 21 (1) ◽

pp. 266 ◽

Cited By ~ 9

Author(s):

Gabriella Schiera ◽

Carlo Maria Di Liegro ◽

Italia Di Liegro

Keyword(s):

Learning And Memory ◽

Extracellular Vesicles ◽

Glial Cells ◽

Information Exchange ◽

System Development ◽

Cell Communication ◽

Nervous System Development ◽

The Body ◽

Pathological Conditions ◽

And Function

Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

Download Full-text

On the Choice of the Extracellular Vesicles for Therapeutic Purposes

International Journal of Molecular Sciences ◽

10.3390/ijms20020236 ◽

2019 ◽

Vol 20 (2) ◽

pp. 236 ◽

Cited By ~ 29

Author(s):

Claudia Campanella ◽

Celeste Caruso Bavisotto ◽

Mariantonia Logozzi ◽

Antonella Marino Gammazza ◽

Davide Mizzoni ◽

...

Keyword(s):

Regenerative Medicine ◽

Extracellular Vesicles ◽

Lipid Membrane ◽

Cell Communication ◽

Membrane Vesicles ◽

Free Form ◽

Target Cells ◽

Disease Biomarkers ◽

Cellular Source ◽

Therapeutic Molecules

Extracellular vesicles (EVs) are lipid membrane vesicles released by all human cells and are widely recognized to be involved in many cellular processes, both in physiological and pathological conditions. They are mediators of cell-cell communication, at both paracrine and systemic levels, and therefore they are active players in cell differentiation, tissue homeostasis, and organ remodeling. Due to their ability to serve as a cargo for proteins, lipids, and nucleic acids, which often reflects the cellular source, they should be considered the future of the natural nanodelivery of bio-compounds. To date, natural nanovesicles, such as exosomes, have been shown to represent a source of disease biomarkers and have high potential benefits in regenerative medicine. Indeed, they deliver both chemical and bio-molecules in a way that within exosomes drugs are more effective that in their exosome-free form. Thus, to date, we know that exosomes are shuttle disease biomarkers and probably the most effective way to deliver therapeutic molecules within target cells. However, we do not know exactly which exosomes may be used in therapy in avoiding side effects as well. In regenerative medicine, it will be ideal to use autologous exosomes, but it seems not ideal to use plasma-derived exosomes, as they may contain potentially dangerous molecules. Here, we want to present and discuss a contradictory relatively unmet issue that is the lack of a general agreement on the choice for the source of extracellular vesicles for therapeutic use.

Download Full-text

Very Long-Chain C24:1 Ceramide Is Increased in Serum Extracellular Vesicles with Aging and Can Induce Senescence in Bone-Derived Mesenchymal Stem Cells

Cells ◽

10.3390/cells8010037 ◽

2019 ◽

Vol 8 (1) ◽

pp. 37 ◽

Cited By ~ 21

Author(s):

Andrew Khayrullin ◽

Priyanka Krishnan ◽

Luis Martinez-Nater ◽

Bharati Mendhe ◽

Sadanand Fulzele ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Cardiovascular Health ◽

Rhesus Macaques ◽

Cell Communication ◽

Size Exclusion ◽

Target Cells ◽

Serum Samples

Extracellular vesicles (EVs), including exosomes and microvesicles, function in cell-to-cell communication through delivery of proteins, lipids and microRNAs to target cells via endocytosis and membrane fusion. These vesicles are enriched in ceramide, a sphingolipid associated with the promotion of cell senescence and apoptosis. We investigated the ceramide profile of serum exosomes from young (24–40 yrs.) and older (75–90 yrs.) women and young (6–10 yrs.) and older (25–30 yrs.) rhesus macaques to define the role of circulating ceramides in the aging process. EVs were isolated using size-exclusion chromatography. Proteomic analysis was used to validate known exosome markers from Exocarta and nanoparticle tracking analysis used to characterize particle size and concentration. Specific ceramide species were identified with lipidomic analysis. Results show a significant increase in the average amount of C24:1 ceramide in EVs from older women (15.4 pmol/sample) compared to those from younger women (3.8 pmol/sample). Results were similar in non-human primate serum samples with increased amounts of C24:1 ceramide (9.3 pmol/sample) in older monkeys compared to the younger monkeys (1.8 pmol/sample). In vitro studies showed that primary bone-derived mesenchymal stem cells (BMSCs) readily endocytose serum EVs, and serum EVs loaded with C24:1 ceramide can induce BMSC senescence. Elevated ceramide levels have been associated with poor cardiovascular health and memory impairment in older adults. Our data suggest that circulating EVs carrying C24:1 ceramide may contribute directly to cell non-autonomous aging.

Download Full-text

Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

Biomolecules ◽

10.3390/biom10091327 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1327 ◽

Cited By ~ 1

Author(s):

Loredana Leggio ◽

Greta Paternò ◽

Silvia Vivarelli ◽

Francesca L’Episcopo ◽

Cataldo Tirolo ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Bioactive Molecules ◽

Substantia Nigra Pars Compacta ◽

Diagnostic Tools ◽

Target Cells ◽

Small Interfering Rnas ◽

Wide Range ◽

Ligand Interactions ◽

The Central Nervous System

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

Download Full-text