31 Current Stem Cell Research & Therapy, 2017, 12, 31-36
REVIEW ARTICLE ISSN: 1574-888X eISSN: 2212-3946
Current Stem Cell Research & Therapy
A Comprehensive Review on Exosomes and Microvesicles as Epigenetic Factors BENTHAM SCIENCE
Behnaz Bakhshandeh*, Mohammad Amin Kamaleddin and Khadijeh Aalishah
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DOI: 10.2174/1574888X11666160709211 528
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Received: December 2, 2015 Revised: June 30, 2016 Accepted: July 5, 2016
Abstract: Exosomes and microvesicles, which are released by most of the cells, play important roles in intracellular correspondence by transferring DNA, messenger RNA, micro RNA, and other types of RNA and proteins. Exosomes and microvesicles may contribute to the distribution of cancers and diseases through delivering the pathogenic agents to the non-infected cells; in cancers, they can modify the cells in the tumor niche and lead them to transformation. In addition, these vesicles can affect stem cell activity and their physiological properties. On the other hand, exosomes and microvesicles can be applied in the therapeutic strategies as they are small, non-viral, flexible and able to cross biological barriers. In this review, we focused on some details about the exosomes and microvesicles both functionally and structurally.
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ARTICLE HISTORY
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Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
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Keywords: Cell communication, epigenetics, metastasis, microvesicles, reprograming.
(messenger RNA), miRNA (micro RNA), membrane receptors and proteins among cells, but also they can induce inflammation [5] and angiogenesis [6] besides their role in cardiovascular disease [5]. The formation of shed vesicles from plasma membrane results in the redistribution of the surface lipids and vertical trafficking of cargo to the places of MV biogenesis [7]. The role of the actin-myosin transport system in mediating the transfer of these multivesicular compartments has been proven [8]. Meanwhile, proteomic analysis of exosomes from different cell types has displayed a common set of the membrane and cytosolic proteins, which suggests the evolutionary significance of these membrane particles [9]. Sources of MVs include the epithelial cells [10], nerve cells [11], B cells [12], T cells [13], muscle cells [14] and platelets [15]. In the further sections, we discuss the main properties of vesicles found in different biological fluids.
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MICROVESICLES AND EXOSOMES
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Microvesicles and exosomes are recently discovered as a novel way of communication between the cells. This property of microvesicles and exosomes is a double-edged sword since they can transfer the information needed for maintaining the physiological balance as well as transferring the information that leads to health disorders. Recently, many researchers have focused on the acquiring them in therapeutic application such as drug delivery, gene delivery, and reshaping injured tissues. In this review, we take a glance on the exosome and microvesicle characterization, their distribution in the body fluids and their different communicative roles between different cells of the body.
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INTRODUCTION
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Exosomes are specialized membranous nano-sized vesicles (50-100 nm) released from the plasma membrane when multivesicular bodies fuse with the cell surface [1, 2]. Microvesicles (MVs) are different from exosomes in that they are usually larger in size (>100 nm) and bud from almost all cell types originally from the cell membrane after activation [3] or during apoptosis [4]. There is also a third group of larger vesicles called apoptotic bodies that are formed during cell death. MVs and exosomes play an important role in intercellular communication. Not only they transfer mRNA
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Urine Different mRNA species are detected in the human urinary MVs [16]. The presence of RNA integrity profile similar to that of kidney tissue (including 18S and 28S ribosomal RNA [17]) has been proven. These vesicles may have a role in protecting RNA during urine passage. Saliva
*Address correspondence to this author at the Department of Biotechnology, College of Science, University of Tehran, P.O. Box: 14155-6455, Tehran, Iran; Tel: +98(21)66491622; Fax: +98-21-66413835; E-mail:
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Many types of small RNA, including small nucleolar RNA, piwi-interacting RNA, miRNA, and mRNA core transcripts [18] are enclosed in salivary exosomes [19]. Interestingly, tumor-shed exosomes are detected both in blood and
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Milk In spite of a high RNase activity in the milk, a considerable amount of mammary gland-related and immune-related small RNAs and miRNAs are present in the milk-derived MVs [22]. Some of these MVs contain mRNA transcripts and possess reverse transcriptase activity [23]. These findings suggest that MVs of bovine breast milk are suitable for being transferred to living cells and are involved in the maturation of many organs. It is hypothesized that retrotransposons may originate from about 14,000 transcriptomes of breast milk MVs. In the other words, RNAs of the breast milk MVs and maternal genomic information can be taken up by the breastfed infant.
Numerous cell surface markers have been found in the vesicles. Exosomes are positive for the marker proteins CD3 [36], CD9 [36-38], CD24 [37], CD63 [36, 38], CD81[38], Annexin-1 [37], Heat-Shock Protein 70 [37] and Early Endosome Antigen 1 protein [39]. In contrast, some tumorderived exosomes contain specific transcripts that could be applied as biomarkers for minimal residual disease diagnostics in peripheral blood [40]. Long noncoding RNAs are enriched in exosomes [41]; moreover, some vesicles contain specific miRNA in a larger proportion than usual which can be utilized as a potential option for new diagnostic techniques [36]. TISSUE-SPECIFIC MVS AND EXOSOMES Nervous System
Neuronal exosomes contain a diverse range of RNA species including retroviral RNA repeat regions, mRNA, tRNA (transfer RNA) fragments, small nuclear RNA, silencing RNA and miRNA [42]. Coordinated interactions between neurons and glial cells guarantee the perfect function of the brain. There is an emerging evidence that exosomes participate in axon-glia communication [43], which is in agreement with previous studies that reveal specific exosomal miRNA expression in brains of patients diagnosed with schizophrenia, bipolar disorder and prion disease [42].
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Investigation of murine species has illustrated that lungderived microvesicles deliver mRNA, transcription factors and miRNA to marrow cells and alter their phenotype [44, 45]. Human nasal lavage fluid [46] and human tracheobronchial epithelial cells [47] also shed exosomes.
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MICROVESICLE CONTENT AND CHARACTERIZATION
Respiratory System
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Three different protocols are applied in order to isolate different membrane-bound vesicles from body fluids: (i) ultracentrifugation-based technique [24], (ii) nano-membrane concentrator-based approach [25], and (iii) utilizing a commercial exosome precipitation reagent [26]. The highest amount of exosomes was achieved using a modified exosome precipitation protocol, which also yielded the highest quantities of miRNA and mRNA. This method is suitable for downstream proteomic analyses if an ultracentrifuge is not available and/or a large number of samples are to be processed [27]. Interestingly, by exposing the exosomes to a non-uniform electrical field, content release and on-site monitoring of the harbored exosomal RNA/proteins biomarkers can be concurrently conducted [20].
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MICROVESICLE ISOLATION
intercellular communication converge at the level of endosomes.
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saliva [20]. These exosomes have specific marker proteins such as CD9, CD63 and CD81 [21] that are necessary for their internalization to the recipient cell.
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Different mechanisms of RNA transportation into vesicles are hypothesized. MiRNAs are released through a ceramide-dependent secretory pathway [28, 29]. While it is generally accepted that the endosomal sorting complex required for transport (ESCRT) is unnecessary for the release of miRNAs [28], one study has revealed that at least the exosomal viral RNA transfer is dependent on ESCRT and Annexin A2 (an RNA-binding protein involved in membrane vesicle trafficking) [30]. Increasing evidence points to the involvement of the multifunctional protein Annexin A2 in the localization of cytoskeleton-bound polysomes [31]. Many researchers proposed that there is a sorting mechanism of miRNAs into exosomes [32, 33]. The miRNA transport mechanisms depend on an incorporation of miRNA into complexes which protect miRNA from abundant RNase activity in the extracellular space [34]. In addition, mature miRNAs, including those of viral origin, are loaded into RNA-induced silencing complexes (RISC) for gene silencing. They trigger mRNA decay during mRNA translation. Recent insights indicate that selective components of RISC (including GW182 and Argonaut proteins) miRNAs and mRNAs are present in the exosomes [35]. Consequently, miRNA function, mRNA stability, and exosome-mediated
The miRNA content of MVs and exosomes could vary in response to different lung disease. For instance, miR-150 levels were meaningfully reduced in circulating MVs in patients with pulmonary arterial hypertension [48]. Another study reported significant differences in 24 miRNAs among healthy people and those with mild asthma [49]; in addition, a substantial difference in total exosome levels has been observed between patients with lung cancer and healthy controls [50]. Reproductive System MVs are present in ovarian follicular fluid and within surrounding granulosa and cumulus cells [51]. MVs released from the endometrial epithelium into the uterine cavity promotes implantation by transferring their contents to either endometrial epithelial cells or to the trophectodermal cells of the blastocyst [36]. Placenta-derived immunosuppressive exosomes may influence a number of mechanisms; for instance, they could promote the fetal allograft survival [52]. Interestingly, exosomes from amniotic fluid have different marker proteins that allow sex determination of the fetus based on the detection of the male-specific ZFY gene product [37].
Exosomes & Microvesicles as Epigenetics Factors
Current Stem Cell Research & Therapy, 2017, Vol. 12, No. 1
Adipocyte-derived microvesicles have angiogenic activity and contain RNA without typical 28S and 18S ribosomal RNA. These vesicles contain most of the transcripts for adipocyte-specific genes such as PPARgamma2, resistin and adiponectin; their abundance is mainly correlated with that of the donor cells [53]. MICROVESICLES IN STEM CELLS
Oncosomes have several surface determinants of tumor cells, e.g. CD29, CD44v7/8, CD51, and chemokine receptors (CCR6, CX3CR1). They are also able to facilitate the escape of tumor cells from immune surveillance through their RNA and protein content [61]. The concentration of tumor-derived vesicles increases in blood plasma and other body fluids with the progression of the disease. Therefore, they may serve as diagnostic symptoms of tumorous cells [62, 63]. Despite of the early reports on no inquiries about existing DNA in MV contents [64], it is now indicated that both viral MVs and tumor MVs may convey DNA such as c-Myc oncogene, that reflects the genetic status of the tumor [65]. Altogether MVs can serve to effectively deliver therapeutic mRNA/proteins to infected cancerous cells [66]. There is no point in denying the fact that using MVs for cancer treatment encounters some barriers, such as transferring of the brainblood barrier and targeted delivery.
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MICROVESICLES AND CANCERS
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The role of extracellular vesicles in transferring genetic material in cancer microenvironment.
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Table 1.
Recent studies has implicated extracellular vesicles in epigenetic regulation such as DNA methylation, histone modification, and miRNA regulation of cancer progression [67]. It has been indicated that many mRNAs and proteins contained in extracellular vesicles are involved in epigenetic regulation [68]. MVs released from leukemia cells increase global DNA methylation levels in recipient cells [69]. Other findings indicate that exosomal mRNAs and proteins participate in histone modification [68, 70]. Another research showed the role of arabidopsis exosome in gene silencing by epigenetic effects on chromatin structure [71]. As mentioned before, detection of epigenetic biomarkers, such as miRNAs, in extracellular vesicles can be
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Oncosomes (special MVs released by cancer cells) contain oncogenic signals or proteins that can be transferred throughout the cancer cell population and to non-transformed stromal cells, endothelial cells and possibly to the inflammatory infiltrates. Various tumor cells emit large quantities of oncosomes [58].
EXOSOME/MICROVESICLE-MEDIATED EPIGENETIC REPROGRAMMING OF THE CELLS
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MVs derived from mesenchymal stem cells and endothelial progenitor cells stimulate proliferation of tubular cells, which causes the morphologic and functional recovery of glycerol-induced acute kidney injury and confers resistance of tubular epithelial cells to apoptosis [56]. These MVs also contain specific proteins such as Stau1 and Stau2, which are associated with the transport and stability of mRNA and Ago2 [34]. Human liver stem cells shed MVs that shuttle mRNAs associated in the control of transcription, translation, proliferation or apoptosis, and translate the transported mRNA into hepatocytes can induce their proliferation subsequently [57].
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MVs, derived from embryonic stem cells, express stem cell-specific molecules that may support self-renewal and expansion of adult stem cells, enhance survival of the hematopoietic stem cell, upregulate the expression of certain markers in these cells, and induce phosphorylation of some enzymes in MAPK/AKT signaling pathway. Furthermore, they play an important role in de-differentiation and pluripotency of Müller cells [54]. It is reported that MVs, as potential carriers of immunogenic and pathogenic compounds, help human embryonic stem cells to communicate [55].
Oncosomes are involved in membrane vesiculation processes, cascades regulated by ABC transporters and intercellular communication [33], as well as various tumor-related pathways such as metastasis, angiogenesis, cancer stem cell hierarchy, intercellular genetic exchange and drug resistance [59, 60].
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Adipose Tissue
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Type of Cargo in Extracellular Vesicle
Role of Cargo in Cancer Microenvironment
Reference
RNA or DNA methyltransferase 3a and 3b
Alteration in expression of tumor-related genes
[69]
G26/24 Oligodendroglioma Cells
Differentiation-specific linker histone H1°
Terminal differentiation, histone modification, and chromatin remodeling
[73]
Metastatic Melanoma Cells
Prominin-1
Metastatic progression
[74]
Metastatic Gastric Cancer Cells
Let-7 miRNA
Induction of a prometastatic phenotype in selected host tissues
[75]
Chronic Myelogenous Leukemia Cells
MiR-126
Modulation of motility and adhesion in endothelial cells
[76]
Bone Marrow Cells
MiR-23b
Promotion breast cancer cell dormancy in a metastatic nich
[77]
Hepatocellular Carcinoma Cells
LncRNA TUC339
Tumor growth, adhesion and cell cycle progression
[78]
Breast Cancer Cells
MALAT1
Tumor metastasis and invasion
[79]
Leukemic Cells
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used for diagnosis of cancer or evaluation of cancer prognosis [72].
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Disease biomarkers, tissue restoration and control of neoplastic cell growth are among the most important aspects of vesicular biology. At this time, using these remarkable properties of MVs, we are able to diagnose cancers and other infectious diseases such as prion disease in a less expensive and more efficient ways. As MVs are non-immunogenic to our immune system, they can be loaded with proteins, DNA and RNA in order to deliver their cargo into the target cells. So, they can be modified for cell type-specific targeting and drug delivery applications. At the same time, these vesicles can be extracted from most body liquids and be manipulated under laboratory conditions which make them promising for therapeutic and prophylactic applications.
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CONCLUSION
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Isolation of MVs with the help of their certain characteristics such as morphology, size, flotation density and the presence of marker proteins will help us to predict the future trend of different diseases. However, difficulties in their sampling and extraction from body fluids, in company with our limited knowledge in medical diagnostic techniques, lead us to the conclusion that more researches need to be done in order to shed more light on the therapeutic aspects and potentials of vesicular biology. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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The binding of miRNAs to Toll-like receptors brings about NF-B signaling pathway activation and secretion of interleukin-6 and Tumor Necrosis Factor , which promote cancer cells growth and metastasis. Immune cells surrounding cancer cells within the tumor microenvironment engulf circulating miRNAs [81]. Exosomes from mast cells have been found to induce dendritic cells maturation and RNA transportation into target cells [82]. The delivered RNA can function as the mRNA to trigger a translation of new proteins in a recipient cell [83]. Some reports have utilized MVassociated miRNA-based therapies using specific mimics/inhibitors of miRNA to treat genetic disease like irritable bowel syndrome [84].
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