The biology, function, and biomedical applications of exosomes

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

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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.

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Zika virus hijacks extracellular vesicle tetraspanin pathways for cell-to-cell transmission

10.1101/2021.03.02.433679 ◽

2021 ◽

Author(s):

Sara B. York ◽

Li Sun ◽

Allaura S. Cone ◽

Leanne C. Duke ◽

Mujeeb R. Cheerathodi ◽

...

Keyword(s):

Extracellular Vesicles ◽

Intercellular Communication ◽

Zika Virus ◽

Biological Fluids ◽

Virus Transmission ◽

First Trimester ◽

Enhanced Production ◽

Infected Cells ◽

Encapsulated Structures

ABSTRACTExtracellular vesicles (EVs) are membrane-encapsulated structures released by cells which carry signaling factors, proteins and microRNAs that mediate intercellular communication. Accumulating evidence supports an important role of EVs in the progression of neurological conditions and both the spread and pathogenesis of infectious diseases. It has recently been demonstrated that EVs from Hepatitis C virus (HCV) infected individuals and cells contained replicative-competent viral RNA that was capable of infecting hepatocytes. Being a member of the same viral family, it is likely the Zika virus also hijacks EV pathways to package viral components and secrete vesicles that are infectious and potentially less immunogenic. As EVs have been shown to cross blood-brain and placental barriers, it is possible that Zika virus could usurp normal EV biology to gain access to the brain or developing fetus. Here, we demonstrate that Zika virus infected cells secrete distinct EV sub-populations with specific viral protein profiles and infectious genomes. Zika virus infection resulted in the enhanced production of EVs with varying sizes and density compared to those released from non-infected cells. We also show that the EV enriched tetraspanin CD63 regulates the release of EVs, and Zika viral genomes and capsids following infection. Overall, these findings provide evidence for an alternative means of Zika virus transmission and demonstrate the role of EV biogenesis and trafficking proteins in the modulation of Zika infection.ImportanceZika virus is a re-emerging infectious disease that spread rapidly across the Caribbean and South America. Infection of pregnant women during the first trimester has been linked to microcephaly, a neurological condition where babies are born with smaller heads due to abnormal brain development. Babies born with microcephaly can develop convulsions and suffer disabilities as they age. Despite the significance of Zika virus, little is known about how the virus infects the fetus or causes disease. Extracellular vesicles (EVs) are membrane-encapsulated structures released by cells that are present in all biological fluids. EVs carry signaling factors, proteins and microRNAs that mediate intercellular communication. EVs have been shown to be a means by which some viruses can alter cellular environments and cross previously unpassable cellular barriers. Thus gaining a greater understanding of how Zika affects EV cargo may aid in the development of better diagnostics, targeted therapeutics and prophylactic treatments.

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Extracellular vesicles in the host-helminth communication: biomedical applications

Anales de la Real Academia Nacional de Farmacia ◽

10.53519/analesranf.2021.87.03.10 ◽

2021 ◽

Vol 87 (87(03)) ◽

pp. 351-360

Author(s):

Antonio Marcilla Díaz

Keyword(s):

Extracellular Vesicles ◽

Biomedical Applications ◽

Lipid Membrane ◽

Biological Fluids ◽

Different Types ◽

Health And Disease ◽

Secretion Of Mediators ◽

New Treatments ◽

Intercellular Communications ◽

Biomedical Interest

Extracellular vesicles participate in intercellular communications, altogether with classic mechanisms like direct contact between cells and the secretion of mediators. They have attracted considerable interest since their discovery in reticulocytes in 1983. The term includes different types of vesicles that vary in size and origin, with exosomes, microvesicles and apoptotic bodies as the major ones. These structures are sorrounded by a lipid membrane, where various types of receptors are located, and can carry different cargo molecules, including sugars, proteins, nucleic acids and metabolites. They have been described in all kingdoms in nature (participating in both intercellular and inter-specific communications), in all types of biological fluids (as part of liquid biopsy). In fact, their presence in samples from both physiological and pathological processes has suggested them as excellent biomarkers. Their role in health and disease is being widely investigated. In this context, the study of extracellular vesicles produced by parasites, and specifically by helminths, constitutes a growing field of research, with great biomedical interest, mainly in the control of infections caused by them. In fact, these vesicles can be used to generate rapid and specific diagnosis systems, to produce new tools for vaccination, and to identify targets for new treatments. The ability of extracellular vesicles to modulate the immune response also opens new possibilities for their use against autoimmune diseases.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2020 ◽

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.

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

Cancers ◽

10.3390/cancers12071964 ◽

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.

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Extracellular Vesicles in the Tumour Microenvironment: Eclectic Supervisors

International Journal of Molecular Sciences ◽

10.3390/ijms21186768 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6768

Author(s):

Claudia Cavallari ◽

Giovanni Camussi ◽

Maria Felice Brizzi

Keyword(s):

Extracellular Vesicles ◽

Immune Escape ◽

Current Knowledge ◽

Cell Communication ◽

Tumour Microenvironment ◽

Cancer Cell Proliferation ◽

Cell Of Origin ◽

Remote Sites ◽

Survival And Growth ◽

Cellular Components

The tumour microenvironment (TME) plays a crucial role in the regulation of cell survival and growth by providing inhibitory or stimulatory signals. Extracellular vesicles (EV) represent one of the most relevant cell-to-cell communication mechanism among cells within the TME. Moreover, EV contribute to the crosstalk among cancerous, immune, endothelial, and stromal cells to establish TME diversity. EV contain proteins, mRNAs and miRNAs, which can be locally delivered in the TME and/or transferred to remote sites to dictate tumour behaviour. EV in the TME impact on cancer cell proliferation, invasion, metastasis, immune-escape, pre-metastatic niche formation and the stimulation of angiogenesis. Moreover, EV can boost or inhibit tumours depending on the TME conditions and their cell of origin. Therefore, to move towards the identification of new targets and the development of a novel generation of EV-based targeting approaches to gain insight into EV mechanism of action in the TME would be of particular relevance. The aim here is to provide an overview of the current knowledge of EV released from different TME cellular components and their role in driving TME diversity. Moreover, recent proposed engineering approaches to targeting cells in the TME via EV are discussed.

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The Significance of Exosomal RNAs in the Development, Diagnosis, and Treatment of Gastric Cancer

Genes ◽

10.3390/genes12010073 ◽

2021 ◽

Vol 12 (1) ◽

pp. 73

Author(s):

Guiping Zhao ◽

Anni Zhou ◽

Xiao Li ◽

Shengtao Zhu ◽

Yongjun Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Average Diameter ◽

Diagnosis And Treatment ◽

Therapeutic Application ◽

Gastric Cancer Cells ◽

The World ◽

Exosomal Rnas

Gastric cancer (GC) is one of the most common malignancies in the world. Exosomes, a subset of extracellular vesicles with an average diameter of 100 nm, contain and transfer a variety of functional macromolecules such as proteins, lipids, and nucleic acids. A large number of studies indicated that exosomes can play a significant role in the initiation and development of GC via facilitating intercellular communication between gastric cancer cells and microenvironment. Exosomal RNAs, one of the key functional cargos, are involved in the pathogenesis, development, and metastasis of GC. In addition, recent studies elucidated that exosomal RNAs may serve as diagnostic and prognostic biomarkers or therapeutic targets for GC. In this review, we summarized the function of exosomal RNA in the tumorigenesis, progression, diagnosis, and treatment of GC, which may further unveil the functions of exosome and promote the potentially diagnostic and therapeutic application of exosomes in GC.

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Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools

Frontiers in Immunology ◽

10.3389/fimmu.2021.682948 ◽

2021 ◽

Vol 12 ◽

Author(s):

Giuseppina Emanuela Grieco ◽

Daniela Fignani ◽

Caterina Formichi ◽

Laura Nigi ◽

Giada Licata ◽

...

Keyword(s):

Type 1 Diabetes ◽

Immune System ◽

Autoimmune Diseases ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Biological Fluids ◽

Β Cells ◽

Pancreatic Β Cells ◽

Disease Biomarkers

Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulin-producing pancreatic β cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic β cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers.

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Current methods for the isolation of extracellular vesicles

Biological Chemistry ◽

10.1515/hsz-2013-0141 ◽

2013 ◽

Vol 394 (10) ◽

pp. 1253-1262 ◽

Cited By ~ 279

Author(s):

Fatemeh Momen-Heravi ◽

Leonora Balaj ◽

Sara Alian ◽

Pierre-Yves Mantel ◽

Allison E. Halleck ◽

...

Keyword(s):

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Magnetic Beads ◽

Cell Types ◽

Target Cells ◽

Cell Of Origin ◽

Novel Technologies ◽

Advantages And Disadvantages ◽

Isolation Methods ◽

Technical Advances

Abstract Extracellular vesicles (EVs), including microvesicles and exosomes, are nano- to micron-sized vesicles, which may deliver bioactive cargos that include lipids, growth factors and their receptors, proteases, signaling molecules, as well as mRNA and non-coding RNA, released from the cell of origin, to target cells. EVs are released by all cell types and likely induced by mechanisms involved in oncogenic transformation, environmental stimulation, cellular activation, oxidative stress, or death. Ongoing studies investigate the molecular mechanisms and mediators of EVs-based intercellular communication at physiological and oncogenic conditions with the hope of using this information as a possible source for explaining physiological processes in addition to using them as therapeutic targets and disease biomarkers in a variety of diseases. A major limitation in this evolving discipline is the hardship and the lack of standardization for already challenging techniques to isolate EVs. Technical advances have been accomplished in the field of isolation with improving knowledge and emerging novel technologies, including ultracentrifugation, microfluidics, magnetic beads and filtration-based isolation methods. In this review, we will discuss the latest advances in methods of isolation methods and production of clinical grade EVs as well as their advantages and disadvantages, and the justification for their support and the challenges that they encounter.

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Molecular Profile Study of Extracellular Vesicles for the Identification of Useful Small “Hit” in Cancer Diagnosis

Applied Sciences ◽

10.3390/app112210787 ◽

2021 ◽

Vol 11 (22) ◽

pp. 10787

Author(s):

Giusi Alberti ◽

Christian M. Sánchez-López ◽

Alexia Andres ◽

Radha Santonocito ◽

Claudia Campanella ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Cancer Metastasis ◽

Biological Fluids ◽

Cell Communication ◽

Response To Treatment ◽

Molecular Profile ◽

Cell Of Origin ◽

Liquid Biopsies ◽

Precision Therapy

Tumor-secreted extracellular vesicles (EVs) are the main mediators of cell-cell communication, permitting cells to exchange proteins, lipids, and metabolites in varying physiological and pathological conditions. They contain signature tumor-derived molecules that reflect the intracellular status of their cell of origin. Recent studies have shown that tumor cell-derived EVs can aid in cancer metastasis through the modulation of the tumor microenvironment, suppression of the immune system, pre-metastatic niche formation, and subsequent metastasis. EVs can easily be isolated from a variety of biological fluids, and their content makes them useful biomarkers for the diagnosis, prognosis, monitorization of cancer progression, and response to treatment. This review aims to explore the biomarkers of cancer cell-derived EVs obtained from liquid biopsies, in order to understand cancer progression and metastatic evolution for early diagnosis and precision therapy.

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