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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 -
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 -
Stem Cell Research & Therapy Mar 2018Mesenchymal stem cells (MSCs) are multipotent stem cells that have gained significant attention in the field of regenerative medicine. The differentiation potential... (Review)
Review
Mesenchymal stem cells (MSCs) are multipotent stem cells that have gained significant attention in the field of regenerative medicine. The differentiation potential along with paracrine properties of MSCs have made them a key option for tissue repair. The paracrine functions of MSCs are applied through secreting soluble factors and releasing extracellular vesicles like exosomes and microvesicles. Extracellular vesicles are predominantly endosomal in origin and contain a cargo of miRNA, mRNA, and proteins that are transferred from their original cells to target cells. Recently it has emerged that extracellular vesicles alone are responsible for the therapeutic effect of MSCs in plenty of animal diseases models. Hence, MSC-derived extracellular vesicles may be used as an alternative MSC-based therapy in regenerative medicine. In this review we discuss MSC-derived extracellular vesicles and their therapeutic potential in various diseases.
Topics: Animals; Extracellular Vesicles; Humans; Mesenchymal Stem Cells; Paracrine Communication; Regenerative Medicine
PubMed: 29523213
DOI: 10.1186/s13287-018-0791-7 -
Current Biology : CB Apr 2018Exosomes and ectosomes, two distinct types of extracellular vesicles generated by all types of cell, play key roles in intercellular communication. The formation of... (Review)
Review
Exosomes and ectosomes, two distinct types of extracellular vesicles generated by all types of cell, play key roles in intercellular communication. The formation of these vesicles depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. These microdomains govern the accumulation of proteins and various types of RNA associated with their cytosolic surface, followed by membrane budding inward for exosome precursors and outward for ectosomes. A fraction of endocytic cisternae filled with vesicles - multivesicular bodies - are later destined to undergo regulated exocytosis, leading to the extracellular release of exosomes. In contrast, the regulated release of ectosomes follows promptly after their generation. These two types of vesicle differ in size - 50-150 nm for exosomes and 100-500 nm for ectosomes - and in the mechanisms of assembly, composition, and regulation of release, albeit only partially. For both exosomes and ectosomes, the surface and luminal cargoes are heterogeneous when comparing vesicles released by different cell types or by single cells in different functional states. Upon release, the two types of vesicle navigate through extracellular fluid for varying times and distances. Subsequently, they interact with recognized target cells and undergo fusion with endocytic or plasma membranes, followed by integration of vesicle membranes into their fusion membranes and discharge of luminal cargoes into the cytosol, resulting in changes to cellular physiology. After fusion, exosome/ectosome components can be reassembled in new vesicles that are then recycled to other cells, activating effector networks. Extracellular vesicles also play critical roles in brain and heart diseases and in cancer, and are useful as biomarkers and in the development of innovative therapeutic approaches.
Topics: Animals; Cell Communication; Cell Membrane; Cell-Derived Microparticles; Exocytosis; Exosomes; Extracellular Vesicles; Humans; Membrane Fusion; Multivesicular Bodies; Signal Transduction
PubMed: 29689228
DOI: 10.1016/j.cub.2018.01.059 -
Pharmacology & Therapeutics Aug 2018Extracellular vesicles (EVs) are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating the tumor-stroma crosstalk. Exosomes are... (Review)
Review
Extracellular vesicles (EVs) are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating the tumor-stroma crosstalk. Exosomes are a subtype of EVs that originate from the limiting membrane of late endosomes, and as such contain information linked to both the intrinsic cell "state" and the extracellular signals cells received from their environment. Resolving the signals affecting exosome biogenesis, cargo sorting and release will increase our understanding of tumorigenesis. In this review we highlight key cell biological processes that couple exosome biogenesis to cargo sorting in cancer cells. Moreover, we discuss how the bidirectional communication between tumor and non-malignant cells affect cancer growth and metastatic behavior.
Topics: Animals; Cell Communication; Exosomes; Extracellular Matrix; Extracellular Vesicles; Humans; Neoplasms; Stromal Cells; Tumor Microenvironment
PubMed: 29476772
DOI: 10.1016/j.pharmthera.2018.02.013 -
Nature Methods Sep 2021Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in... (Review)
Review
Extracellular vesicles (EVs) are nano-sized lipid bilayer vesicles released by virtually every cell type. EVs have diverse biological activities, ranging from roles in development and homeostasis to cancer progression, which has spurred the development of EVs as disease biomarkers and drug nanovehicles. Owing to the small size of EVs, however, most studies have relied on isolation and biochemical analysis of bulk EVs separated from biofluids. Although informative, these approaches do not capture the dynamics of EV release, biodistribution, and other contributions to pathophysiology. Recent advances in live and high-resolution microscopy techniques, combined with innovative EV labeling strategies and reporter systems, provide new tools to study EVs in vivo in their physiological environment and at the single-vesicle level. Here we critically review the latest advances and challenges in EV imaging, and identify urgent, outstanding questions in our quest to unravel EV biology and therapeutic applications.
Topics: Animals; Coloring Agents; Epitopes; Extracellular Vesicles; Fluorescent Dyes; Humans; Microscopy
PubMed: 34446922
DOI: 10.1038/s41592-021-01206-3 -
Cellular and Molecular Neurobiology Apr 2016Extracellular vesicles are a heterogeneous group of membrane-limited vesicles loaded with various proteins, lipids, and nucleic acids. Release of extracellular vesicles... (Review)
Review
Extracellular vesicles are a heterogeneous group of membrane-limited vesicles loaded with various proteins, lipids, and nucleic acids. Release of extracellular vesicles from its cell of origin occurs either through the outward budding of the plasma membrane or through the inward budding of the endosomal membrane, resulting in the formation of multivesicular bodies, which release vesicles upon fusion with the plasma membrane. The release of vesicles can facilitate intercellular communication by contact with or by internalization of contents, either by fusion with the plasma membrane or by endocytosis into "recipient" cells. Although the interest in extracellular vesicle research is increasing, there are still no real standards in place to separate or classify the different types of vesicles. This review provides an introduction into this expanding and complex field of research focusing on the biogenesis, nucleic acid cargo loading, content, release, and uptake of extracellular vesicles.
Topics: Animals; Biological Transport; Exosomes; Extracellular Vesicles; Humans; Models, Biological; RNA
PubMed: 27053351
DOI: 10.1007/s10571-016-0366-z -
Molecular Therapy : the Journal of the... May 2021Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo...
Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.
Topics: Animals; Cell Communication; Drug Delivery Systems; Extracellular Vesicles; Female; HEK293 Cells; Humans; Membrane Proteins; Mice; Neoplasm Proteins; Nerve Tissue Proteins; Proteins; Repressor Proteins
PubMed: 33484965
DOI: 10.1016/j.ymthe.2021.01.020 -
Blood Jun 2021Platelets play significant and varied roles in cancer progression, as detailed throughout this review series, via direct interactions with cancer cells and by long-range... (Review)
Review
Platelets play significant and varied roles in cancer progression, as detailed throughout this review series, via direct interactions with cancer cells and by long-range indirect interactions mediated by platelet releasates. Microvesicles (MVs; also referred to as microparticles) released from activated platelets have emerged as major contributors to the platelet-cancer nexus. Interactions of platelet-derived MVs (PMVs) with cancer cells can promote disease progression through multiple mechanisms, but PMVs also harbor antitumor functions. This complex relationship derives from PMVs' binding to both cancer cells and nontransformed cells in the tumor microenvironment and transferring platelet-derived contents to the target cell, each of which can have stimulatory or modulatory effects. MVs are extracellular vesicles of heterogeneous size, ranging from 100 nm to 1 µm in diameter, shed by living cells during the outward budding of the plasma membrane, entrapping local cytosolic contents in an apparently stochastic manner. Hence, PMVs are encapsulated by a lipid bilayer harboring surface proteins and lipids mirroring the platelet exterior, with internal components including platelet-derived mature messenger RNAs, pre-mRNAs, microRNAs, and other noncoding RNAs, proteins, second messengers, and mitochondria. Each of these elements engages in established and putative PMV functions in cancer. In addition, PMVs contribute to cancer comorbidities because of their roles in coagulation and thrombosis and via interactions with inflammatory cells. However, separating the effects of PMVs from those of platelets in cancer contexts continues to be a major hurdle. This review summarizes our emerging understanding of the complex roles of PMVs in the development and progression of cancer and cancer comorbidities.
Topics: Animals; Blood Platelets; Cell Communication; Extracellular Vesicles; Humans; Neoplasms; RNA, Neoplasm; Tumor Microenvironment
PubMed: 33940593
DOI: 10.1182/blood.2019004119 -
Extracellular vesicles in cardiovascular disease: Biological functions and therapeutic implications.Pharmacology & Therapeutics May 2022Extracellular vesicles (EVs), including exosomes and microvesicles, are lipid bilayer particles naturally released from the cell. While exosomes are formed as... (Review)
Review
Extracellular vesicles (EVs), including exosomes and microvesicles, are lipid bilayer particles naturally released from the cell. While exosomes are formed as intraluminal vesicles (ILVs) of the multivesicular endosomes (MVEs) and released to extracellular space upon MVE-plasma membrane fusion, microvesicles are generated through direct outward budding of the plasma membrane. Exosomes and microvesicles have same membrane orientation, different yet overlapping sizes; their cargo contents are selectively packed and dependent on the source cell type and functional state. Both exosomes and microvesicles can transfer bioactive RNAs, proteins, lipids, and metabolites from donor to recipient cells and influence the biological properties of the latter. Over the last decade, their potential roles as effective inter-tissue communicators in cardiovascular physiology and pathology have been increasingly appreciated. In addition, EVs are attractive sources of biomarkers for the diagnosis and prognosis of diseases, because they acquire their complex cargoes through cellular processes intimately linked to disease pathogenesis. Furthermore, EVs obtained from various stem/progenitor cell populations have been tested as cell-free therapy in various preclinical models of cardiovascular diseases and demonstrate unequivocally encouraging benefits. Here we summarize the findings from recent research on the biological functions of EVs in the ischemic heart disease and heart failure, and their potential as novel diagnostic biomarkers and therapeutic opportunities.
Topics: Biomarkers; Cardiovascular Diseases; Cell Communication; Cell-Derived Microparticles; Exosomes; Extracellular Vesicles; Humans
PubMed: 34687770
DOI: 10.1016/j.pharmthera.2021.108025