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Biochimica Et Biophysica Acta. Reviews... Dec 2018Extracellular vesicles (EVs) including exosomes, microvesicles, oncosomes, and microparticles have been associated with communicating anti-cancer drug-resistance. The in... (Review)
Review
Extracellular vesicles (EVs) including exosomes, microvesicles, oncosomes, and microparticles have been associated with communicating anti-cancer drug-resistance. The in vitro, pre-clinical in vivo and patients' data linking EVs to drug-resistance (and the specific drugs involved) in breast cancer, prostate cancer, lung cancer, ovarian cancer, haematological malignancies, colorectal cancer, gastric cancer, pancreatic cancer, glioblastoma, neuroblastoma, melanoma, kidney cancer and osteosarcoma. Details of the mechanisms by which the resistance seems to be occurring (e.g. EVs transferring drug-efflux pumps from drug-resistant cancer cells, EVs binding monoclonal antibodies in the peripheral circulation and so reducing their bioavailability, EVs from tumour microenvironment cells, etc.) are outlined, as are efforts to try to block such resistance. Research to date strongly supports EVs as playing a key role in drug-resistance. Further studies including tailored clinical studies are now warranted to determine how best to prevent this occurring, in the interest of patients and also for economic benefit. Furthermore, efforts to exploit safe (non-cancer origin) EVs as anti-cancer drug delivery vehicles that may achieve efficacy with more limited side-effects than free drug, deserve further investigation.
Topics: Animals; Drug Resistance, Neoplasm; Extracellular Vesicles; Humans; Neoplasms; Tumor Microenvironment
PubMed: 30003999
DOI: 10.1016/j.bbcan.2018.07.003 -
Cells Dec 2019There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs).... (Review)
Review
There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.
Topics: Animals; Exosomes; Extracellular Vesicles; Humans; Inflammation; Mesenchymal Stem Cells; Oxidative Stress
PubMed: 31835680
DOI: 10.3390/cells8121605 -
Sub-cellular Biochemistry 2021In the final stages of apoptosis, apoptotic cells can generate a variety of membrane-bound vesicles known as apoptotic extracellular vesicles (ApoEVs). Apoptotic bodies...
In the final stages of apoptosis, apoptotic cells can generate a variety of membrane-bound vesicles known as apoptotic extracellular vesicles (ApoEVs). Apoptotic bodies (ApoBDs), a major subset of ApoEVs, are formed through a process termed apoptotic cell disassembly characterised by a series of tightly regulated morphological steps including plasma membrane blebbing, apoptotic membrane protrusion formation and fragmentation into ApoBDs. To better characterise the properties of ApoBDs and elucidate their function, a number of methods including differential centrifugation, filtration and fluorescence-activated cell sorting were developed to isolate ApoBDs. Furthermore, it has become increasingly clear that ApoBD formation can contribute to various biological processes such as apoptotic cell clearance and intercellular communication. Together, recent literature demonstrates that apoptotic cell disassembly and thus, ApoBD formation, is an important process downstream of apoptotic cell death. In this chapter, we discuss the current understandings of the molecular mechanisms involved in regulating apoptotic cell disassembly, techniques for ApoBD isolation, and the functional roles of ApoBDs in physiological and pathological settings.
Topics: Apoptosis; Extracellular Vesicles
PubMed: 33779914
DOI: 10.1007/978-3-030-67171-6_4 -
Molecular Therapy : the Journal of the... May 2023Extracellular vesicles (EVs) are gaining increasing attention for diagnostic and therapeutic applications in various diseases. These natural nanoparticles benefit from... (Review)
Review
Extracellular vesicles (EVs) are gaining increasing attention for diagnostic and therapeutic applications in various diseases. These natural nanoparticles benefit from favorable safety profiles and unique biodistribution capabilities, rendering them attractive drug-delivery modalities over synthetic analogs. However, the widespread use of EVs is limited by technological shortcomings and biological knowledge gaps that fail to unravel their heterogeneity. An in-depth understanding of their biogenesis is crucial to unlocking their full therapeutic potential. Here, we explore how knowledge about EV biogenesis can be exploited for EV bioengineering to load therapeutic protein or nucleic acid cargos into or onto EVs. We summarize more than 75 articles and discuss their findings on the formation and composition of exosomes and microvesicles, revealing multiple pathways that may be stimulation and/or cargo dependent. Our analysis further identifies key regulators of natural EV cargo loading and we discuss how this knowledge is integrated to develop engineered EV biotherapeutics.
Topics: Tissue Distribution; Extracellular Vesicles; Exosomes; Cell-Derived Microparticles; Bioengineering
PubMed: 36805147
DOI: 10.1016/j.ymthe.2023.02.013 -
Nature Reviews. Molecular Cell Biology Oct 2020The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment... (Review)
Review
The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications.
Topics: Animals; Biological Transport; Cell Communication; Extracellular Vesicles; Humans; Mammals; RNA
PubMed: 32457507
DOI: 10.1038/s41580-020-0251-y -
Current Protocols Jan 2022Extracellular vesicles (EVs) in plants have emerged as key players in cell-to-cell communication and cross-kingdom RNAi between plants and pathogens by facilitating the...
Extracellular vesicles (EVs) in plants have emerged as key players in cell-to-cell communication and cross-kingdom RNAi between plants and pathogens by facilitating the exchange of RNA, proteins, and other molecules. In addition to their role in intercellular communication, plant EVs also show promise as potential therapeutics and indicators of plant health. However, plant EVs exhibit significant heterogeneity in their protein markers, size, and biogenesis pathways, strongly influencing their composition and functionality. While mammalian EVs can be generally classified as exosomes that are derived from multivesicular bodies (MVBs), microvesicles that are shed from the plasma membrane, or as apoptotic bodies that originate from cells undergoing apoptosis, plant EVs remain poorly studied in comparison. At least three subclasses of EVs have been identified in Arabidopsis leaves to date, including Tetraspanin-positive exosomes derived from MVBs, Penetration 1 (PEN1)-positive EVs, and EVs derived from exocyst-positive organelles (EXPO). Differences in the plant starting material and isolation techniques have resulted in different purities, quality, and compositions of the resulting EVs, complicating efforts to better understand the role of these EVs in plants. We performed a comparative analysis on commonly used plant EV isolation methods and have identified an effective protocol for extracting clean apoplastic washing fluid (AWF) and isolating high-quality intact and pure EVs of Arabidopsis thaliana. These EVs can then be used for various applications or studied to assess their cargos and functionality in plants. Furthermore, this process can be easily adapted to other plant species of interest. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Isolation of EVs from the apoplastic fluid of Arabidopsis thaliana Basic Protocol 2: Density gradient fractionation of EVs Basic Protocol 3: Immuno-isolation of EVs using Arabidopsis tetraspanin 8 (TET8) antibody.
Topics: Animals; Arabidopsis; Cell-Derived Microparticles; Exosomes; Extracellular Vesicles; Plant Leaves
PubMed: 35030291
DOI: 10.1002/cpz1.352 -
Cell Research Sep 2018In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of...
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3 mice to show that reduction of apoptotic body formation significantly impaired the self-renewal and osteo-/adipo-genic differentiation of bone marrow mesenchymal stem cells (MSCs). Systemic infusion of exogenous apoptotic bodies rescued the MSC impairment and also ameliorated the osteopenia phenotype in MRL/lpr, Caspase 3 and ovariectomized (OVX) mice. Mechanistically, we showed that MSCs were able to engulf apoptotic bodies via integrin αvβ3 and reuse apoptotic body-derived ubiquitin ligase RNF146 and miR-328-3p to inhibit Axin1 and thereby activate the Wnt/β-catenin pathway. Moreover, we used a parabiosis mouse model to reveal that apoptotic bodies participated in the circulation to regulate distant MSCs. This study identifies a previously unknown role of apoptotic bodies in maintaining MSC and bone homeostasis in both physiological and pathological contexts and implies the potential use of apoptotic bodies to treat osteoporosis.
Topics: Animals; Apoptosis; Bone Diseases, Metabolic; Cell Differentiation; Cell Proliferation; Extracellular Vesicles; Female; Homeostasis; Mesenchymal Stem Cells; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout
PubMed: 30030518
DOI: 10.1038/s41422-018-0070-2 -
Seminars in Cell & Developmental Biology Apr 2015Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an... (Review)
Review
Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an important role in cancer. The state of knowledge on biogenesis, molecular content and horizontal communication of diverse types of cancer EVs has expanded considerably in recent years. As a consequence, a plethora of information about EV composition and molecular function has emerged, along with the notion that cancer cells rely on these particles to invade tissues and propagate oncogenic signals at distance. The number of in vivo studies, designed to achieve a deeper understanding of the extent to which EV biology can be applied to clinically relevant settings, is rapidly growing. This review summarizes recent studies on cancer-derived EV functions, with an overview about biogenesis and molecular cargo of exosomes, microvesicles and large oncosomes. We also discuss current challenges and emerging technologies that might improve EV detection in various biological systems. Further studies on the functional role of EVs in specific steps of cancer formation and progression will expand our understanding of the diversity of paracrine signaling mechanisms in malignant growth.
Topics: Animals; Cell-Derived Microparticles; Exosomes; Extracellular Vesicles; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 25721812
DOI: 10.1016/j.semcdb.2015.02.010 -
Molecular Cancer Mar 2019The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current... (Review)
Review
The tumor microenvironment represents a complex network, in which tumor cells not only communicate with each other but also with stromal and immune cells. Current research has demonstrated the vital role of the tumor microenvironment in supporting tumor phenotype via a sophisticated system of intercellular communication through direct cell-to-cell contact or by classical paracrine signaling loops of cytokines or growth factors. Recently, extracellular vesicles have emerged as an important mechanism of cellular interchange of bioactive molecules. Extracellular vesicles isolated from tumor and stromal cells have been implicated in various steps of tumor progression, such as proliferation, angiogenesis, metastasis, and drug resistance. Inhibition of extracellular vesicles secretion, and thus of the transfer of oncogenic molecules, holds promise for preventing tumor growth and drug resistance. This review focuses on the role of extracellular vesicles in modulating the tumor microenvironment by addressing different aspects of the bidirectional interactions among tumor and tumor-associated cells. The contribution of extracellular vesicles to drug resistance will also be discussed as well as therapeutic strategies targeting extracellular vesicles production for the treatment of cancer.
Topics: Animals; Antineoplastic Agents; Cell Communication; Drug Resistance, Neoplasm; Extracellular Vesicles; Humans; Neoplasms; Tumor Microenvironment
PubMed: 30925923
DOI: 10.1186/s12943-019-0965-7 -
International Journal of Molecular... Sep 2020Extracellular vesicles (EVs) are membranous vesicles secreted by both prokaryotic and eukaryotic cells and play a vital role in intercellular communication. EVs are... (Review)
Review
Extracellular vesicles (EVs) are membranous vesicles secreted by both prokaryotic and eukaryotic cells and play a vital role in intercellular communication. EVs are classified into several subtypes based on their origin, physical characteristics, and biomolecular makeup. Exosomes, a subtype of EVs, are released by the fusion of multivesicular bodies (MVB) with the plasma membrane of the cell. Several methods have been described in literature to isolate exosomes from biofluids including blood, urine, milk, and cell culture media, among others. While differential ultracentrifugation (dUC) has been widely used to isolate exosomes, other techniques including ultrafiltration, precipitating agents such as poly-ethylene glycol (PEG), immunoaffinity capture, microfluidics, and size-exclusion chromatography (SEC) have emerged as credible alternatives with pros and cons associated with each. In this review, we provide a summary of commonly used exosomal isolation techniques with a focus on SEC as an ideal methodology. We evaluate the efficacy of SEC to isolate exosomes from an array of biological fluids, with a particular focus on its application to adipose tissue-derived exosomes. We argue that exosomes isolated via SEC are relatively pure and functional, and that this methodology is reproducible, scalable, inexpensive, and does not require specialized equipment or user expertise. However, it must be noted that while SEC is a good candidate method to isolate exosomes, direct comparative studies are required to support this conclusion.
Topics: Animals; Chromatography, Gel; Exosomes; Extracellular Vesicles; Humans; Ultracentrifugation; Ultrafiltration
PubMed: 32899828
DOI: 10.3390/ijms21186466