- Review
- Open access
- Published:
Roles of extracellular microRNAs in central nervous system
ExRNA volume 1, Article number: 13 (2019)
Abstract
MicroRNAs are small non-coding RNAs containing about 18–25 nucleotides which modulate gene expression post-transcriptionally. Recently, microRNAs have been detected in the extracellular space including a wide range of body fluids. These extracellular miRNAs, often encapsulated in secreted extracellular vesicles, can be transferred into recipient cells and thus inhibits the expression of targeted genes. In view of these findings, a new exosome-based therapeutic approach is invented, which can effectively deliver miRNAs/siRNAs into specific cells. In central nervous system, extracellular miRNAs can not only be used as noninvasive biomarkers for diagnosis of several neurological disorders, but also mediate the intercellular communication between neurons and glial cells. In this review, we will discuss the latest research work regarding the roles of secreted miRNAs in central nervous system and evaluate the potential of exosome-mediated miRNAs/siRNAs delivery in neural therapy.
MicroRNAs in the central nervous system
The biogenesis and turnover of miRNAs
MicroRNAs (miRNAs) are 18–25 nucleotide noncoding RNAs that modulates gene expression by posttranscription regulation, which in turn lead to consequent biological functions [1]. Precursor miRNA molecule (pri-miRNA) is originally produced in the nucleus, where it is further processed by a complex of RNase. Afterwards, pre-miRNA is generated and sequentially carried out by exportin 5. Once transported into the cytoplasm, pre-miRNA forms a hairpin structure which is further digested by the RNase Dicer. The cleavage results in a double-stranded small RNA and one of which is the mature miRNA [2, 3]. The strand of mature miRNA is incorporated into RNA-induced silencing complex (RISC), which is known as a multi-protein RNA complex [4]. This is indispensable for their capacity of modulating protein expression, in which a seed sequence (6–8 nucleotides) of the miRNA binds to the 3′ UTR region of mRNAs to repress translation. In mammalian cells, about 30–60% proteins are targeted by miRNAs, among which they are involved in various biological processes that control cell proliferation, differentiation, regeneration, as well as apoptosis [1, 5,6,7]. In contrary to the biogenesis of miRNAs, the degradation of miRNAs receives limited attention so far. When the concentration of targeted mRNAs is very low, the miRNAs will detach from the RISC and enters into degradation process [8]. The cellular level of miRNAs is controlled by both production and degradation. It is suggested that the period for miRNA degradation is much longer than that of messenger RNA [9]. Furthermore, recent evidences have showed that miRNAs can be steadily exited in the extracellular system which will be discussed in the next chapter [10].
Classical functions of miRNAs in neural system
A large number of miRNAs are expressed in the Central nervous system (CNS), regulating several important proteins which further affects both physiological and pathological process in CNS [11, 12]. It enables us to overview the general effects of miRNAs in CNS by genetic deletion of essential enzymes for miRNA biogenesis. For instance, mice that lack of dicer at E18.5 display abnormal migration of late-born neurons in the cortex as well as affected expansion of oligodendrocyte precursor in the spinal cord [13]. Besides, individual roles of miRNAs have also been widely studied. There are several studies suggesting that miR-9 and miR-124 positively regulate neurogenesis [14]. Several miRNAs also show time and space dependent expression pattern during the development of CNS. Schratt et al. has demonstrated that miR-134 is expressed in dendrites in hippocampal neurons, which modulates dendritic spine development by targeting LIMK1 [15]. Among these biological process, there is one thing in common that those miRNAs and targeted mRNAs are both generated in the same cell. The miRNA-mRNA regulation works in a cell-autonomous manner.
Extracellular microRNAs
Extracellular microRNAs in body fluid as disease biomarker
In general thought, RNAs are highly unstable, which can be easily degraded in a very short time after their biogenesis. Until two independent groups (Chen, et al. and Mitchell, et al.) claimed their findings of miRNAs in serum/plasma, it is hard to believe that miRNA can be existed in such environment full of RNAse [16, 17]. These investigations formally start the research of extracellular RNAs. Afterwards, these cell-free miRNAs are detected in more and more body fluids samples such as saliva, urine and even milk [18,19,20]. Nevertheless, the level of these circulating miRNAs are closely related to a variety of disease processes, including cancers, tissue injuries and even neural degeneration diseases, indicating the potential of circulating miRNAs as non-invasive diagnostic markers for these diseases [21, 22].
Regarding to the findings of circulating miRNAs, the source of these extracellular miRNAs is still unknown. One possible source is the passive leakage from the injury tissue or broken cells, which still lacks direct evidences. It is demonstrated that the exogenous plant miRNAs increase in serum and other tissues after the mice were fed with rice or honeysuckle [23, 24]. These results suggest another explanation that serum miRNAs maybe, at least, part of the result of active secretion from tissue cells.
Secreted microRNAs in extracellular vesicles
Extracellular vesicles (EVs) have small membranous structure, which are secreted from cell to extracellular space in both physiological and pathological conditions. EVs have once been considered as non-functional debris from broken cells [25]. Until recently, a series of investigations show that EVs shedding is involved in intercellular communication [26,27,28]. EVs are composed of shedding vesicles (SVs) and exosomes, these two groups have different discharging processes as well as their body size [29]. Shedding vesicles are generated during the surface shedding from the plasma membrane (100-500 nm), while the production of exosomes are totally different, which are derived from multivesicular bodies secreted into extracellular space by exocytosis (30-80 nm) [30]. EVs are presented in not only the medium of cell culture but also most part of body fluids, including serum/plasma, saliva, urine as well as milk, which largely overlaps with where secreted miRNAs were found [31]. In addition, it is reported that EVs contains lipids, cytosolic proteins, messenger RNAs and even miRNAs, indicating miRNAs in EVs may be the main source of that found in body fluids [32]. It is suggested that the proportion of miRNA in EVs is about 5% of that in cytoplasm [33].
Functions of secreted microRNAs
The molecules in EVs mentioned above can be transported into the recipient cells leading to further biological functions [22]. MiRNAs are one of these most important molecules enriched in EVs. For instance, embryonic stem cells released EVs that contain large amount of miRNAs, which can be further delivered into the recipient cells in vitro [34, 35]. Once delivered into target cells, miRNAs will show their great capacity in the modulation of protein expression. Zhang et al. have demonstrated that exosomes transfer miR-150 into endothelial cells, which inhibits c-Myb translation in target cells and increase the recipient cell migration [36]. In addition, Yin et al. have showed that miR-214 secreted by tumor cells can enter CD4+ T cells, repressing local expression of PTEN and thus affecting Treg proliferation [37]. Another group suggests that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury [38]. The way of such intercellular miRNA-mRNA regulation has been found in a wide range of biological processes [10]. Additionally, secreted miRNAs may also be involved in fetal–maternal crosstalk as we found that immune-related miRNAs are enriched in colostrum EVs [18, 39, 40]. Furthermore, several studies demonstrated that exosomes derived from placenta mediate the communication between fetus and mother, showing the immune regulatory effects [41, 42]. Moreover, there are evidences that exogenous miRNAs can be absorbed through the gastrointestinal track indicating that extracellular miRNAs may even mediate the interaction between species [43]. Zhang et al. have demonstrated that exogenous plant MIR168a can be absorbed and delivered into the liver of mice fed with rice, where it specifically targets mammalian LDLRAP1 [23]. Zhou et al. provided evidences that after oral administration of honeysuckle, plant MIR2911 can enter the mice tissues, especially lungs, which remarkably inhibited H1N1 viral replication [24]. Together, these results suggest that secreted miRNAs have non-cell autonomous effects which is different with its classical roles inside the cells.
Extracellular microRNAs in the central nervous system
Circulating miRNAs in neurological disorders as diagnostic biomarkers
Since circulating miRNAs within blood and other biofluids can be detected and accurately quantified, they showed great potentials in application of disease diagnosis as non-invasive biomarkers [44, 45]. The panel of serum miRNAs may also be associated with the disease progression for neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS).
In PD patients, the profiling of serum miRNA revealed that miR-1, miR-22p, and miR-29a were significantly reduced compared with healthy controls. In addition, the level of miR-16-2-3p, miR-26a-2-3p, and miR-30a in serum can tell whether these PD patients receive treatment [46]. Later, it is demonstrated that five serum miRNAs can make a distinction between PD patients and normal controls, while another research group [47], Dong et al. even showed that 4-miRNA panel in serum help to distinguish different stages of PD patients from normal individuals [48]. In addition to the differential expression of circulating miRNAs, Kasandra et al. also detected potential novel miRNAs in blood and cerebrospinal fluid from AD and PD patients. In their investigation, the level of extracellular miRNAs detected in body fluids showed remarkable changes with different illnesses status, which indicates those extracellular miRNAs finger prints may help the diagnosis of the disease at different stages [49]. While in the case of AD, four serum miRNAs including miR-31, miR-93, miR-143, and miR-146a are significantly reduced compared to normal controls [50]. Another work revealed serum miR-223 as a promising diagnostic marker for AD. Additionally, the differential expression of miR-125b and miR-223 together may assist the early diagnosis of AD [51]. One research about ALS model reveals that miR-206 is up-regulated in skeletal muscles as well as plasma [52]. Furthermore, investigation of two intendent cohorts of ALS patients demonstrated that two circulating miRNAs (miR-4299 and miR-4649-5p) were markedly altered [53]. Besides, there are also evidences showing the association between circulating miRNAs and magnetic resonance imaging measurement of multiple sclerosis (MS) severity indicating that serum miRNAs are also significantly changed in MS patients. The alteration of serum miRNA levels could help to the evaluation of MS subtype and progression [54, 55].
Except for neurodegenerative diseases, circulating miRNAs were also used as biomarkers in acute neural injury, brain tumors and even neuropsychiatric disorders. Recently, a panel of serum miRNAs were found to differentiate mild and severe traumatic brain injury (TBI) patients [56]. In addition, elevated level of secreted miRNAs in serum is strongly related to the pathogenesis of ischemic stroke [57]. Another study in in 2017 by Wu et al. demonstrated that a panel of 3-miRNAs in serum can clearly distinguish ischemic stroke from transient ischemic attack patients [58]. In middle cerebral artery occlusion rat model, the differential expression of serum miRNAs provide strong advantage in evaluating the severity of neural injury during stroke pathology [59]. High-grade gliomas are the most aggressive and devastating brain tumors. Circulating miRNAs are appealing biomolecules which may facilitate the diagnosis of such malignant gliomas. In blood of glioblastoma patients, compared with controls, miR-128 overexpression has been identified [60]. Furthermore, Regazzo et al. suggested that serum miRNAs are potentially applicable in the diagnosis of malignant gliomas, which can precisely tell the differences between glioblastoma and slow-growing gliomas [61]. The alteration of circulating miRNAs has also been linked with several neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. Vasu et al. have demonstrated that thirteen serum miRNAs are significantly changed in ASD patients, among which five miRNAs are enough to help the differential diagnosis of ASD [62]. In the investigation of schizophrenia patients, it is also reported that plasma miRNAs are abnormally expressed in disease group compared with healthy controls, indicating the great potential of circulating miRNAs in evaluating the disease progression [63]. Taken together, these investigations suggest that circulating miRNAs are promising biomolecules for the differential diagnosis of neurological disorders.
Role of extracellular miRNAs in physiological and pathological condition in CNS
Substantial evidence indicates that EVs, especially exosomes produced via cell exocytosis, can transport messenger RNAs, miRNAs as well as proteins into target cells, mediating the intercellular communication [32]. In the central nervous system, both neurons and glial cells can release EVs, which has been considered to be a new mode to maintain homeostasis [64].
In healthy neurons, EVs play an important role in local and possibly interneuronal exchanging of small biomolecules. In one specific scenario, both synaptic RNAs and proteins can be transported across the synapse via exosomes, which further modulates synaptic plasticity [65]. In addition, Xu et al. showed that synaptosomes can release and uptake miRNAs in different physiological conditions, indicating the miRNAs secretion in synapse may be a novel mode of communication between neurons [66]. Moreover, it is also indicated that synaptic vesicles contain miRNAs, which indicates the role of secreted miRNAs in modulating local protein translation at synaptic terminals [67]. Neurons can not only secret miRNAs but also react with extracellular miRNAs as it is reported that miRNAs in extracellular space can bind to neuronal TLR7 and thus activate nociceptor neurons [68].
There are also abundant miRNAs in exosomes derived from astrocyte, which showed different expression pattern from that of parent cells, indicating a selective package of miRNAs from cytoplasm into exosomes [69]. Those packaged miRNAs may mediate neuron-glia interaction both in physiological and pathological condition. Carlos et al. proposed that miRNAs in astrocytic exosomes can be delivered into neuronal cells, which may contribute to the regulation of neural plasticity [70]. Another study reveals that miR-34a in shedding vesicles generated from astrocyte can be delivered into dopaminergic neurons, and thus enhanced neuronal loss under neurotoxic stress by downregulation of BCL-2 in target cells [33]. Furthermore, it is also reported that astrocytic exosomes can transfer miRNAs into metastatic tumor cells, which inhibit the expression of PTEN and prime brain metastasis outgrowth in vivo [71].
In microglia, secreted miRNAs also play key roles in mediated neuron-glia communication. EVs shed from M1 polarized microglia contain high level of miR-375, which inhibits the expression of PDK1 and increases neuronal injury in recipient cells [72]. Besides, pro-inflammatory miRNAs which include miR-146a and miR-155 are also increased in EVs derived from those M1 polarized cells, indicating the possible role of secreted miRNAs in the dissemination of inflammatory responses in brain [73].
In addition to the exosomes derived from normal cells, one study provided direct visual evidence that extracellular vesicles produced by glioblastoma deliver miR-21 into microglia and decrease the targeted mRNA level of c-Myc in vivo [74]. Nevertheless, secreted miRNAs in exosomes can even contribute to the communication between brain and blood. Systemic inflammation induced an increase of pro-inflammatory miRNAs in EVs derived from choroid plexus, which are received by glial cells, enhancing the downstream inflammatory responses [75]. Another work shows that environmental enrichment stimulates the production of pro-myelinating exosomes that contain high level of miR-219 from immune cells, which further promote CNS myelination [76].
Together, these results suggest a distinctive role of secreted miRNAs in mediating intercellular communication in CNS as well as the interaction between blood and brain.
Therapeutic potential of secreted miRNAs/siRNAs in neurological disorders
Over the last decades, EVs, especially exosomes have been used to deliver small functional molecules in the therapy for several diseases including neurodegenerative disorders [32]. Exosomes are emerging as mediators not only of neurodegeneration, but also of neuroprotection. They were shown to be involved in the regeneration and recovery after peripheral neural injury as well as neuronal damages in CNS [77]. Furthermore, their capability to cross the blood–brain barrier provides us great advantage to use them as delivery vehicles for neurological disorders [78, 79]. In one breakthrough study, wood’s group used self-derived exosome from dendritic cells, which carry a fusion protein that links Lamp2b with the rabies virus glycoprotein (RVG) peptide with neuron specificity, to deliver siRNA into brain through intravenously injection. Those engineered exosomes showed great capacity in crossing blood–brain barrier and delivery of exogenous siRNA into neural cells, which results in a specific knockdown of BACE1 [78]. Newly studies also demonstrate that exosomes based therapy can alleviate neuroinflammation, increase neurogenesis and angiogenesis, which further improve spatial learning after TBI in animal models [80,81,82]. Another encouraging series of findings suggested that the expression level of miR-133b in MSCs significantly upregulated after exposing to ischemic conditions, which can be further transmitted into neurons and astroglia by MSC-derived exosomes, consequently promoting neurite growth and recovery of brain function [83,84,85]. In addition to the effect of secreted miRNAs on neurite remodeling, exosomal miRNAs also have the potential to modulate neuronal differentiation. It is demonstrated that miR-124 can be delivered into neural precursor cells (NPCs) through exosome, which downregulated the protein level of Sox9 and promoted the neurogenesis from the NPCs [86]. These studies together provide some methodology references and enlightenments for the exploration of extracellular miRNAs delivery strategy in the CNS.
Conclusion
The study of extracellular miRNAs in CNS is an exciting area that has aroused strong research interest. In addition to their great potential in the differential diagnosis of neurological disorders, secreted miRNAs represent a novel mode of intercellular communication in both physiological and pathological conditions, suggesting a new level of complexity in information transmission and processing within the neural system. Nevertheless, the transport of exogenous miRNAs into recipient cells by exosomes also suggests their application in the delivery of RNA-based therapeutics. It is of great significance to make deeper understanding of extracellular miRNAs mediated intercellular communication as well as mechanisms of their package, release and uptake, which will improve diagnostic and therapeutic strategy in CNS diseases.
Abbreviations
- AD:
-
Alzheimer’s disease
- ALS:
-
Amyotrophic lateral sclerosis
- ASD:
-
Autism spectrum disorder
- CNS:
-
Central nervous system
- EVs:
-
Extracellular vesicles
- MS:
-
Multiple sclerosis
- MSCs:
-
Mesenchymal stem cells
- NPCs:
-
Neural precursor cells
- PD:
-
Parkinson’s disease
- RISC:
-
RNA-induced silencing complex
- RVG:
-
Rabies virus glycoprotein
- SVs:
-
Shedding vesicles
- TBI:
-
Traumatic brain injury
References
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.
Fontana F, Siva K, Denti MA. A network of RNA and protein interactions in Fronto temporal dementia. Front Mol Neurosci. 2015;8:9.
Zhang Y, Wang XF. Post-transcriptional regulation of MTA family by microRNAs in the context of cancer. Cancer Metastasis Rev. 2014;33(4):1011–6.
Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ. Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004;305(5689):1437–41.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20.
Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105.
Huang S, He X. microRNAs: tiny RNA molecules, huge driving forces to move the cell. Protein cell. 2010;1(10):916–26.
Ruegger S, Grosshans H. MicroRNA turnover: when, how, and why. Trends Biochem Sci. 2012;37(10):436–46.
Gantier MP, McCoy CE, Rusinova I, Saulep D, Wang D, Xu D, Irving AT, Behlke MA, Hertzog PJ, Mackay F, et al. Analysis of microRNA turnover in mammalian cells following Dicer1 ablation. Nucleic Acids Res. 2011;39(13):5692–703.
Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22(3):125–32.
Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12(9):735–9.
Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS. A microRNA array reveals extensive regulation of microRNAs during brain development. Rna. 2003;9(10):1274–81.
Kawase-Koga Y, Otaegi G, Sun T. Different timings of dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system. Dev Dyn. 2009;238(11):2800–12.
Radhakrishnan B, Alwin Prem Anand A. Role of miRNA-9 in brain development. J Exp Neurosci. 2016;10:101–20.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439(7074):283–9.
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513–8.
Sun Q, Chen X, Yu J, Zen K, Zhang CY, Li L. Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum. Protein Cell. 2013;4(3):197–210.
Chen X, Liang H, Zhang J, Zen K, Zhang CY. Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell. 2012;3(1):28–37.
Zhu H, Fan GC. Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am J Cardiovasc Dis. 2011;1(2):138–49.
Ghai V, Wang K. Recent progress toward the use of circulating microRNAs as clinical biomarkers. Arch Toxicol. 2016;90(12):2959–78.
Yamamoto S, Azuma E, Muramatsu M, Hamashima T, Ishii Y, Sasahara M. Significance of extracellular vesicles: Pathobiological roles in disease. Cell Struct Funct. 2016;41(2):137–43.
Zhang L, Hou D, Chen X, Li D, Zhu L, Zhang Y, Li J, Bian Z, Liang X, Cai X, et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res. 2012;22(1):107–26.
Zhou Z, Li X, Liu J, Dong L, Chen Q, Liu J, Kong H, Zhang Q, Qi X, Hou D, et al. Honeysuckle-encoded atypical microRNA2911 directly targets influenza a viruses. Cell Res. 2015;25(1):39–49.
Morel MC, Newcombe JR, Swindlehurst JC. The effect of age on multiple ovulation rates, multiple pregnancy rates and embryonic vesicle diameter in the mare. Theriogenology. 2005;63(9):2482–93.
Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A. 2009;106(10):3794–9.
Gupta A, Pulliam L. Exosomes as mediators of neuroinflammation. J Neuroinflammation. 2014;11:68.
Shantsila E, Kamphuisen PW, Lip GY. Circulating microparticles in cardiovascular disease: implications for atherogenesis and atherothrombosis. J Thromb Haemost. 2010;8(11):2358–68.
Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, et al. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 2009;28(8):1043–54.
Zomer A, Vendrig T, Hopmans ES, van Eijndhoven M, Middeldorp JM, Pegtel DM. Exosomes: fit to deliver small RNA. Communicative Integr Biol. 2010;3(5):447–50.
Lagana A, Russo F, Veneziano D, Bella SD, Giugno R, Pulvirenti A, Croce CM, Ferro A. Extracellular circulating viral microRNAs: current knowledge and perspectives. Front Genet. 2013;4:120.
Jiang XC, Gao JQ. Exosomes as novel bio-carriers for gene and drug delivery. Int J Pharm. 2017;521(1–2):167–75.
Mao S, Sun Q, Xiao H, Zhang C, Li L. Secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neurons to neurotoxins by targeting Bcl-2. Protein Cell. 2015;6(7):529–40.
Katsman D, Stackpole EJ, Domin DR, Farber DB. Embryonic stem cell-derived microvesicles induce gene expression changes in Muller cells of the retina. PLoS One. 2012;7(11):e50417.
Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, Farber DB. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4(3):e4722.
Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, Sun F, Lu J, Yin Y, Cai X, et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell. 2010;39(1):133–44.
Yin Y, Cai X, Chen X, Liang H, Zhang Y, Li J, Wang Z, Chen X, Zhang W, Yokoyama S, et al. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res. 2014;24(10):1164–80.
Kamalden TA, Macgregor-Das AM, Kannan SM, Dunkerly-Eyring B, Khaliddin N, Xu Z, Fusco AP, Yazib SA, Chow RC, Duh EJ, et al. Exosomal MicroRNA-15a transfer from the pancreas augments diabetic complications by inducing oxidative stress. Antioxid Redox Signal. 2017;27(13):913–30.
Chen T, Xi QY, Ye RS, Cheng X, Qi QE, Wang SB, Shu G, Wang LN, Zhu XT, Jiang QY, et al. Exploration of microRNAs in porcine milk exosomes. BMC Genomics. 2014;15:100.
Kosaka N, Izumi H, Sekine K, Ochiya T. microRNA as a new immune-regulatory agent in breast milk. Silence. 2010;1(1):7.
Mincheva-Nilsson L, Baranov V. Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success. Am J Reprod Immunol. 2014;72(5):440–57.
Salomon C, Rice GE. Role of exosomes in placental homeostasis and pregnancy disorders. Prog Mol Biol Transl Sci. 2017;145:163–79.
Liang H, Zhang S, Fu Z, Wang Y, Wang N, Liu Y, Zhao C, Wu J, Hu Y, Zhang J, et al. Effective detection and quantification of dietetically absorbed plant microRNAs in human plasma. J Nutr Biochem. 2015;26(5):505–12.
Parrizas M, Novials A. Circulating microRNAs as biomarkers for metabolic disease. Best Pract Res Clin Endocrinol Metab. 2016;30(5):591–601.
Pant K, Venugopal SK. Circulating microRNAs: possible role as non-invasive diagnostic biomarkers in liver disease. Clinics and research in hepatology and gastroenterology. 2017;41(4):370–377.
Margis R, Margis R, Rieder CR. Identification of blood microRNAs associated to Parkinsonis disease. J Biotechnol. 2011;152(3):96–101.
Ding H, Huang Z, Chen M, Wang C, Chen X, Chen J, Zhang J. Identification of a panel of five serum miRNAs as a biomarker for Parkinson's disease. Parkinsonism Relat Disord. 2016;22:68–73.
Dong H, Wang C, Lu S, Yu C, Huang L, Feng W, Xu H, Chen X, Zen K, Yan Q, et al. A panel of four decreased serum microRNAs as a novel biomarker for early Parkinson's disease. Biomarkers. 2016;21(2):129–37.
Burgos K, Malenica I, Metpally R, Courtright A, Rakela B, Beach T, Shill H, Adler C, Sabbagh M, Villa S, et al. Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. PLoS One. 2014;9(5):e94839.
Dong H, Li J, Huang L, Chen X, Li D, Wang T, Hu C, Xu J, Zhang C, Zen K, et al. Serum MicroRNA profiles serve as novel biomarkers for the diagnosis of Alzheimer’s disease. Dis Markers. 2015;2015:625659.
Jia LH, Liu YN. Downregulated serum miR-223 servers as biomarker in Alzheimer's disease. Cell Biochem Funct. 2016;34(4):233–7.
Toivonen JM, Manzano R, Olivan S, Zaragoza P, Garcia-Redondo A, Osta R. MicroRNA-206: a potential circulating biomarker candidate for amyotrophic lateral sclerosis. PLoS One. 2014;9(2):e89065.
Takahashi I, Hama Y, Matsushima M, Hirotani M, Kano T, Hohzen H, Yabe I, Utsumi J, Sasaki H. Identification of plasma microRNAs as a biomarker of sporadic amyotrophic lateral sclerosis. Mol Brain. 2015;8(1):67.
Kacperska MJ, Walenczak J, Tomasik B. Plasmatic microRNA as potential biomarkers of multiple sclerosis: literature review. Adv Clin Exp Med. 2016;25(4):775–9.
Regev K, Paul A, Healy B, von Glenn F, Diaz-Cruz C, Gholipour T, Mazzola MA, Raheja R, Nejad P, Glanz BI, et al. Comprehensive evaluation of serum microRNAs as biomarkers {Selvamani, 2014 #2} {Mundalil Vasu, 2014 #4} in multiple sclerosis. Neurol(R) Neuroimmunol Neuroinflammation. 2016;3(5):e267.
Bhomia M, Balakathiresan NS, Wang KK, Papa L, Maheshwari RK. A panel of serum MiRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Sci Rep. 2016;6:28148.
Wu J, Du K, Lu X. Elevated expressions of serum miR-15a, miR-16, and miR-17-5p are associated with acute ischemic stroke. Int J Clin Exp Med. 2015;8(11):21071–9.
Wu J, Fan CL, Ma LJ, Liu T, Wang C, Song JX, Lv QS, Pan H, Zhang CN, Wang JJ. Distinctive expression signatures of serum microRNAs in ischaemic stroke and transient ischaemic attack patients. Thromb Haemost. 2017;117(05):992–1001.
Selvamani A, Williams MH, Miranda RC, Sohrabji F. Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model. Clin Sci. 2014;127(2):77–89.
Sun J, Liao K, Wu X, Huang J, Zhang S, Lu X. Serum microRNA-128 as a biomarker for diagnosis of glioma. Int J Clin Exp Med. 2015;8(1):456–63.
Regazzo G, Terrenato I, Spagnuolo M, Carosi M, Cognetti G, Cicchillitti L, Sperati F, Villani V, Carapella C, Piaggio G, et al. A restricted signature of serum miRNAs distinguishes glioblastoma from lower grade gliomas. J Exp Clin Cancer Res. 2016;35(1):124.
Mundalil Vasu M, Anitha A, Thanseem I, Suzuki K, Yamada K, Takahashi T, Wakuda T, Iwata K, Tsujii M, Sugiyama T, et al. Serum microRNA profiles in children with autism. Mol Autism. 2014;5:40.
Wei H, Yuan Y, Liu S, Wang C, Yang F, Lu Z, Wang C, Deng H, Zhao J, Shen Y, et al. Detection of circulating miRNA levels in schizophrenia. Am J Psychiatry. 2015;172(11):1141–7.
Pegtel DM, Peferoen L, Amor S. Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos Trans R Soc Lond B Biol Sci. 2014;369(1652):20130516.
Smalheiser NR. Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol Direct. 2007;2:35.
Xu J, Chen Q, Zen K, Zhang C, Zhang Q. Synaptosomes secrete and uptake functionally active microRNAs via exocytosis and endocytosis pathways. J Neurochem. 2013;124(1):15–25.
Li H, Wu C, Aramayo R, Sachs MS, Harlow ML. Synaptic vesicles contain small ribonucleic acids (sRNAs) including transfer RNA fragments (trfRNA) and microRNAs (miRNA). Sci Rep. 2015;5:14918.
Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, Ji RR. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron. 2014;82(1):47–54.
Jovicic A, Gitler AD. Distinct repertoires of microRNAs present in mouse astrocytes compared to astrocyte-secreted exosomes. PLoS One. 2017;12(2):e0171418.
Lafourcade C, Ramirez JP, Luarte A, Fernandez A, Wyneken U. MiRNAs in astrocyte-derived exosomes as possible mediators of neuronal plasticity. J Exp Neurosci. 2016;10(Suppl 1):1–9.
Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527(7576):100–4.
Tang LL, Wu YB, Fang CQ, Qu P, Gao ZL. NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. Biochem Biophys Res Commun. 2016;469(3):392–8.
Cunha C, Gomes C, Vaz AR, Brites D. Exploring new inflammatory biomarkers and pathways during LPS-induced M1 polarization. Mediat Inflamm. 2016;2016:6986175.
van der Vos KE, Abels ER, Zhang X, Lai C, Carrizosa E, Oakley D, Prabhakar S, Mardini O, Crommentuijn MH, Skog J, et al. Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro-oncology. 2016;18(1):58–69.
Balusu S, Van Wonterghem E, De Rycke R, Raemdonck K, Stremersch S, Gevaert K, Brkic M, Demeestere D, Vanhooren V, Hendrix A, et al. Identification of a novel mechanism of blood-brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Mol Med. 2016;8(10):1162–83.
Pusic KM, Pusic AD, Kraig RP. Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell Mol Neurobiol. 2016;36(3):313–25.
Lopez-Verrilli MA, Picou F, Court FA. Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia. 2013;61(11):1795–806.
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.
Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, Jiang X, Hou D, Chen X, Chen Y, et al. Targeted exosome-mediated delivery of opioid receptor mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543.
Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122(4):856–67.
Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ. Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A. 2016;113(1):170–5.
Zhang Y, Chopp M, Zhang ZG, Katakowski M, Xin H, Qu C, Ali M, Mahmood A, Xiong Y. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int. 2017;111:69–81.
Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556–64.
Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33(11):1711–5.
Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31(12):2737–46.
Lee HK, Finniss S, Cazacu S, Xiang C, Brodie C. Mesenchymal stem cells deliver exogenous miRNAs to neural cells and induce their differentiation and glutamate transporter expression. Stem Cells Dev. 2014;23(23):2851–61.
Acknowledgements
Not applicable.
Funding
This work was supported by grants from the National Natural Science Foundation of China (31471019).
Availability of data and materials
Not applicable.
Author information
Authors and Affiliations
Contributions
LL conceived the original idea. LL and WJ co-wrote and co-edited the final version of the manuscript. Both authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Li, L., Wang, J. Roles of extracellular microRNAs in central nervous system. ExRNA 1, 13 (2019). https://doi.org/10.1186/s41544-019-0011-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s41544-019-0011-3