Extracellular vesicles as an emerging mechanism of

Authors: Ciro Tetta Ezio Ghigo Lorenzo Silengo Maria Chiara Deregibus Giovanni Camussi

Publish Date: 2012/12/01

Volume: 44, Issue: 1, Pages: 11-19

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Abstract

The concept that extracellular vesicles may act as paracrine/endocrine effectors is based on the evidence that they are able to transport bioactive molecules between cells either within a defined microenvironment or remotely by entering the biologic fluids Extracellular vesicles including exosomes and microvesicles may deliver lipids and various functional transcripts released from the cell of origin to target cells Since extracellular vesicles contain defined patterns of mRNA microRNA long noncoding RNA and occasionally genomic DNA they may transfer genetic information which induces transient or persistent phenotypic changes in recipient cells In this review we will discuss potential physiologic and pathological implications of extracellular vesicles as well as the diagnostic and therapeutic opportunities that they may provideCells are required to communicate with each other for appropriate development and functioning of tissues Classical means of cell communication are represented by cell junctions adhesion contacts and soluble factors that can act upon the same cell where they are produced or upon neighboring cells or may even act over long distances in an endocrine manner 1 In addition to these described means another mechanism of cell communication has recently emerged namely communication by extracellular vesicles EVs EVs are released by numerous cell types such as blood cells dendritic cells endothelial and epithelial cells nervous cells tumor cells and embryonic and adult stem cells in the extracellular space both in physiologic and pathological conditions EVs have also been identified in body fluids such as serum saliva amniotic fluid synovial fluid breast milk and urine 2 3 4 5 6 7 Cell communication by means of EVs is described as being a universal way for cells to interact with each other and influence the behavior of other cells by exchanging material and informationEVs are cytosol fragments with spheroid morphology surrounded by a membrane composed of a lipid bilayer and hydrophilic proteins similar to the cell plasma membrane EVs are a heterogeneous group of vesicles known in the literature by several different names microvesicles microparticles ectosomes exosomes shedding vesicles etc with sizes ranging from 30 to 1000 nm They are constitutively produced in vitro or in vivo by cells or following the activation by soluble agonists or physical or chemical stress including oxidative stress hypoxia and shear stress 8 Since EVs carry receptors bioactive lipids proteins and most importantly nucleic acids such as mRNA and microRNA miRNA they are able to deliver important information to recipient cells The delivery of mRNA to target cells is followed by subsequent transcription and production of functional proteins Moreover functional miRNA may interfere with the production of target proteins within recipient cells Consequently EVs may modify the phenotype and functions of target cellsThe exact process of EV formation is currently not fully elucidated The previous classification of EVs into the two major groups of shedding vesicles and exosomes on the basis of their different biogenesis size and protein composition is presently controversial and recent studies have questioned its validityIt has been suggested that shedding vesicles may originate by direct budding from the cell plasma membrane into the extracellular space in a calciumdependent process with cytoskeleton reorganization curvaturemediated lateral redistribution of membrane components leading to the creation of rafts and membrane nanodomains and formation of plasmamediated attractive forces between membranes 9The instrumental role of sphingomyelinases SMases has been reported in the mechanism of EV release It has recently been demonstrated that acidicSMase ASMase is involved in microparticle release in glial cells and thus represents a crucial role in EV release ASMase activity triggers microparticle release from glial cells 10On the other hand exosomes are thought to originate from the endosomal membrane cell compartment and their release is said to be consequential to the exocytosis of multivesicular bodies and discharge into the extracellular space of intraluminal vesicles after fusion with the plasma membrane in a p53controlled process and is dependent on cytoskeleton activation but independent of cell calcium concentration In addition some studies have suggested that the multiprotein complex Endosomal Sorting Complexes Required for Transport ESCRT has a critical role in the sorting of vesicles and the finding of certain components of the ESCRT complex in exosomes such as Alix and Tsg101 has raised the possibility that the ESCRT machinery could be involved in the formation and exocytosis of these vesicles 11 12Trajkovich et al 13 have recently suggested a different pathway for intraendosomal membrane transport and exosome formation in a mouse oligodendroglial cell line independent of the ESCRT machinery but requiring sphingolipid ceramide Ceramide is one of the major lipids in the lipid bilayer of cell membranes and is produced after hydrolysis of sphingomyelin catalyzed by SMases and used for the generation of intraluminal vesicles of multivesicular bodies that are not intended for transfer to lysosomes and subsequent degradation but are released as exosomes 13

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