Extracellular Communication Research Articles

Quorum quenching inhibits the formation and electroactivity of electrogenic biofilm by weakening intracellular c-di-GMP and extracellular AHL-mediated signal communication.

Electrogenic biofilm formation has been shown to be induced by intracellular c-di-GMP signaling and extracellular quorum sensing, but their interactions have been rarely explored. This study explored the effects of quorum quenching (induced by adding acylase) on electrogenic biofilm development and its underlying mechanisms. Quorum quenching impaired the electricity generation and electroactivity of electrogenic biofilms as indicated by dye decolorization rate. It significantly decreased the proportion of typical exoelectrogen Geobacter from 62.0% to 36.5% after 90 days of operation, and enriched some other functional genera (e.g., Dysgonomonas and Sphaerochaeta) to ensure normal physiological function. Moreover, metagenomic analysis revealed that the addition of acylase weakened the potential of chemical communication, as indicated by the decrease in the abundance of genes encoding the production of AHL and c-di-GMP, and the increase in the abundance of aiiA and pvdQ genes (encoding quorum quenching) and cdgC gene (responsible for c-di-GMP breakdown). Functional contribution analysis indicated that Geobacter was a major contributor to hdtS gene (encoding AHL synthesis). These findings demonstrated that quorum quenching adversely impaired not only quorum sensing but also intracellular c-di-GMP signaling, ultimately inhibiting the development of biofilm. This work lays the foundation for regulating electrogenic biofilm development and improving the performance of microbial electrochemical system using signal communication strategy.

Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.

In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.

Potential Use of Selected Natural Compounds with Anti-Biofilm Activity.

Antibiotic resistance in microorganisms is an escalating global concern, exacerbated by their formation of biofilms, which provide protection through an extracellular matrix and communication via quorum sensing, enhancing their resistance to treatment. This situation has driven the search for alternative approaches, particularly those using natural compounds. This study explores the potential of phytochemicals, such as quercetin, apigenin, arbutin, gallic acid, proanthocyanidins, and rutin, known for their antibacterial properties and ability to inhibit biofilm formation and disrupt mature biofilms. The methods used in this study included a comprehensive review of current literature assessing the bioavailability, distribution, and effective concentrations of these compounds in treating biofilm-associated infections. The results indicate that these phytochemicals exhibit significant antibacterial effects, reduce biofilm's structural integrity, and inhibit bacterial communication pathways. Moreover, their potential use in combination with existing antibiotics may enhance therapeutic outcomes. The findings support the conclusion that phytochemicals offer promising additions to anti-biofilm strategies and are capable of complementing or replacing conventional treatments, with appropriate therapeutic levels and delivery mechanisms being key to their effectiveness. This insight underscores the need for further research into their clinical applications for treating infections complicated by biofilms.

Extracellular RNA communication: A decade of NIH common fund support illuminates exRNA biology.

The discovery that extracellular RNAs (exRNA) can act as endocrine signalling molecules established a novel paradigm in intercellular communication. ExRNAs can be transported, both locally and systemically in virtually all body fluids. In association with an array of carrier vehicles of varying complexity, exRNA can alter target cell phenotype. This highlights the important role secreted exRNAs have in regulating human health and disease. The NIH Common Fund exRNA Communication program was established in 2012 to accelerate and catalyze progress in the exRNA biology field. The program addressed both exRNA and exRNA carriers, and served to generate foundational knowledge for the field from basic exRNA biology to future potential clinical applications as biomarkers and therapeutics. To address scientific challenges, the exRNA Communication program developed novel tools and technologies to isolate exRNA carriers and analyze their cargo. Here, we discuss the outcomes of the NIH Common Fund exRNA Communication program, as well as the evolution of exRNA as a scientific field through the analysis of scientific publications and NIH funding. ExRNA and associated carriers have potential clinical use as biomarkers, diagnostics, and therapeutics. Recent translational applications include exRNA-related technologies repurposed as novel diagnostics in response to the COVID-19 pandemic, the clinical use of extracellular vesicle-based biomarker assays, and exRNA carriers as drug delivery platforms. This comprehensive landscape analysis illustrates how discoveries and innovations in exRNA biology are being translated both into the commercial market and the clinic. Analysis of program outcomes and NIH funding trends demonstrate the impact of this NIH Common Fund program.

InTiCAR: Network-based identification of significant inter-tissue communicators for autoimmune diseases.

Inter-tissue communicators (ITCs) are intricate and essential aspects of our body, as they are the keepers of homeostatic equilibrium. It is no surprise that the dysregulation of the exchange between tissues are at the core of various disorders. Among such conditions, autoimmune diseases (AIDs) refer to a collection of pathological conditions where the miscommunication drives the immune system to mistakenly attack one's own body. Due to their myriad and diverse pathophysiologies, AIDs cannot be easily diagnosed or treated, and continuous efforts are required to seek for potential diagnostic markers or therapeutic targets. The identification of ITCs with significant involvement in the disease states is therefore crucial. Here, we present InTiCAR, Inter-Tissue Communicators for Autoimmune diseases by Random walk with restart, which is a network exploration-based analysis method that suggests disease-specific ITCs based on prior knowledge of disease genes, without the need for the external expression data. We first show that distinct ITC profile s can be acquired for various diseases by InTiCAR. We further illustrate that, for autoimmune diseases (AIDs) specifically, the disease-specific ITCs outperform disease genes in diagnosing patients using the UK Biobank plasma proteome dataset. Also, through CMap LINCS dataset, we find that high perturbation on the AIDs genes can be observed by the disease-specific ITCs. Our results provide and highlight unique perspectives on biological network analysis by focusing on the entities of extracellular communications.

Evolution of Bioelectric Membrane Potentials: Implications in Cancer Pathogenesis and Therapeutic Strategies.

Electrophysiology typically deals with the electrical properties of excitable cells like neurons and muscles. However, all other cells (non-excitable) also possess bioelectric membrane potentials for intracellular and extracellular communications. These membrane potentials are generated by different ions present in fluids available in and outside the cell, playing a vital role in communication and coordination between the cell and its organelles. Bioelectric membrane potential variations disturb cellular ionic homeostasis and are characteristic of many diseases, including cancers. A rapidly increasing interest has emerged in sorting out the electrophysiology of cancer cells. Compared to healthy cells, the distinct electrical properties exhibited by cancer cells offer a unique way of understanding cancer development, migration, and progression. Decoding the altered bioelectric signals influenced by fluctuating electric fields benefits understanding cancer more closely. While cancer research has predominantly focussed on genetic and molecular traits, the delicate area of electrophysiological characteristics has increasingly gained prominence. This review explores the historical exploration of electrophysiology in the context of cancer cells, shedding light on how alterations in bioelectric membrane potentials, mediated by ion channels and gap junctions, contribute to the pathophysiology of cancer.

Gla Rich Protein (GRP) Mediates Vascular Smooth Muscle Cell (VSMC) Osteogenic Differentiation, Extracellular Vesicle (EV) Calcification Propensity, and Immunomodulatory Properties.

Vascular calcification (VC) is a complex process involving vascular smooth muscle cell (VSMC) osteogenic differentiation, inflammation, and extracellular vesicle (EV) calcification and communication networks. Gla rich protein (GRP) is a calcification inhibitor involved in most of these processes. However, the molecular mechanism of GRP in VC and the specific characteristics, cargo, and functionality of calcifying EVs require further elucidation. Here, we use a combination of human ex vivo aortic fragments and primary vascular smooth muscle cell (VSMC) models to obtain new information on GRP function in VC and EVs released by VSMCs. We demonstrate that GRP inhibits VSMC osteogenic differentiation through downregulation of bone-related proteins and upregulation of mineralization inhibitors, with decreased mineral crystallinity in EVs deposited into the tissue extracellular matrix (ECM). EVs isolated by ultracentrifugation at 30K and 100K from the cell media (CM) and deposited in the ECM from control (CTR) and mineralizing (MM) VSMCs were biochemically, physically, and proteomically characterized. Four different EV populations were identified with shared markers commonly present in all EVs but with unique protein cargo and specific molecular profiles. Comparative proteomics identified several regulated proteins specifically loaded into MM EV populations associated with multiple processes involved in VC. Functional analysis demonstrated that 30K and 100K ECM-MM EVs with higher calcium and lower GRP levels induced macrophage inflammation. Our findings reinforce the functional relevance of GRP in multiple VC processes and suggest that ECM EVs released under calcification stress function as a new signaling axis on the calcification-inflammation cycle.

Adaptive responses of skeletal muscle to calcaneal tendon partial injury in rats: insights into remodeling and plasticity.

Skeletal muscle is a highly adaptive tissue, capable of responding to different physiological and functional demands, even in situations that may cause instability. To evaluate how partial calcaneal tendon (CT) injuries affect the remodeling and plasticity of the gastrocnemius muscle over time. The study was carried out with Wistar rats randomly divided into five groups. The control group comprised animals not subjected to partial CT damage. The remaining four groups were subjected to partial CT damage and were further categorized based on the time of euthanasia: 3, 14, 28, and 55 days after injury. The gastrocnemius muscle was collected and used for gene expression analysis, zymography, flow cytometry, and morphology. The calcaneal tendon was analyzed only to verify the presence of the partial injury. The impact of partial CT injury on the gastrocnemius homeostasis, particularly on gene expression, was more pronounced in the 3-day group compared to the other groups, especially the control group. Cytokine profile and morphologic alterations occurred in the 55 days group when compared to the other groups. The data reported here suggest that partial injury can negatively affect intracellular signaling and degradation pathways, disturbing the muscular extracellular matrix regulatory mechanisms and communication with the tendon. However, skeletal muscle seems to mitigate these harmful effects in comparison with lesions that affect muscle and tendon.

Extracellular Vesicles Contribute to Oxidized LDL-Induced Stromal Cell Proliferation in Benign Prostatic Hyperplasia.

Clinical and experimental evidence has linked Benign Prostatic Hyperplasia (BPH) with dyslipidemic and hypercholesterolemic conditions, though the underlying cellular mechanisms remain unclear. This study investigates the impact of dyslipidemia, specifically oxidized LDL (OxLDL), on prostatic stromal cell proliferation and the release of extracellular vesicles (EVs). Mice were fed a high-fat diet, and human prostatic stromal cells (HPSCs) were treated with OxLDL. Proliferation assays and EV characterization were performed to assess the role of EVs in BPH progression. Pro-atherogenic conditions significantly increased cell proliferation in both murine prostatic cells and HPSCs. Treatment with metformin effectively inhibited OxLDL-induced proliferation. Additionally, OxLDL stimulated the production and release of pro-proliferative EVs by HPSCs, which further promoted cellular proliferation. The findings suggest that dyslipidemia drives prostatic stromal cell proliferation and EV secretion, contributing to BPH progression. Metformin demonstrates potential as a therapeutic agent to mitigate these effects, offering insight into novel strategies for BPH management. This study highlights the complex interaction between dyslipidemia, cell proliferation, and extracellular communication in the context of BPH pathogenesis.

Extracellular Vesicle-Mediated Neuron-Glia Communications in the Central Nervous System.

Communication between neurons and glia significantly influences the development maturation, plasticity, and disease progressions of the nervous system. As a new signaling modality, extracellular vesicles display a diverse role for robust functional regulation of neurons through their protein and nucleic acid cargoes. This review highlights recent breakthroughs in the research of signaling mechanisms between glia and neurons mediated by extracellular vesicles that are important for neural development, axonal maintenance, synaptic functions, and disease progression in the mammalian nervous system. We will discuss the biological roles of extracellular vesicles released from neurons, astroglia, microglia, and oligodendroglia in the nervous system and their implications in neurodegenerative disorders.

Investigation of cell-to-cell transfer of polystyrene microplastics through extracellular vesicle-mediated communication

Plastics are an essential part of human life and their production is increasing every year. Plastics degrade into small particles (<5 mm, microplastics, MPs) in the environment due to various factors. MPs are widely distributed in the environment, and all living organisms are exposed to the effects of MPs. Extracellular vesicles (EVs) are small membrane particles surrounded by a lipid bilayer that are released into the environment by various cell types and are highly involved in inter- and intra-cellular communication through the exchange of proteins, nucleic acids, and lipids between cells. There have been numerous reports of adverse effects associated with the accumulation of MPs in human and animal cells, with recent studies showing that plastic treatment increases the number of EVs released from cells, but the mechanisms by which MPs accumulate and move between cells remain unclear. In this study, we investigated whether polystyrene (PS)-MPs are transferred cell-to-cell via EVs. This study showed that cell-derived EVs can transport plastic particles. Furthermore, we confirmed the accumulation of PS-MPs transported by EVs within cells using a real-time imaging device. This study provides an understanding of potential EVs-mediated effects of PS-MPs on organisms and suggests directions for further research.

Exosome-transmitted circ_0004664 suppresses the migration and invasion of cadmium-transformed human bronchial epithelial cells by regulating PTEN expression via miR-942-5p

Exosomes play a crucial role in regulating extracellular communication between normal and cancer cells within the tumor microenvironment, thereby affecting tumor progression through their cargo molecules. However, the specific impact of exosomal circular RNAs (circRNAs) on the development of cadmium-induced carcinogenesis remains unclear. To address this, we investigated whether exosomes derived from normal human bronchial epithelial BEAS-2B (N–B2B) cells could transmit circRNA to cadmium-transformed BEAS-2B (Cd–B2B) cells and the potential effects on Cd–B2B cells. Our findings demonstrated a significant downregulation of circ_0004664 in Cd–B2B cells compared to N–B2B cells (P < 0.01). Overexpression of circ_0004664 in Cd–B2B cells led to a significant inhibition of cell migration and invasion (P < 0.01 or P < 0.05). Furthermore, N–B2B cells could transfer circ_0004664 into recipient Cd–B2B cells via exosomes, subsequently inhibiting cell migration and invasion (P < 0.05 or P < 0.01). Mechanistic investigations revealed that exosomal circ_0004664 functioned as a competitive endogenous RNA for miR-942-5p, resulting in an upregulation of PTEN (P < 0.05). Our study highlights the involvement of exosomal circ_0004664 in cell-cell communication during cadmium carcinogenesis, providing a novel insight into the role of exosomal circRNA in this process.

Sulfamoylated Estradiol Analogs Targeting the Actin and Microtubule Cytoskeletons Demonstrate Anti-Cancer Properties In Vitro and In Ovo.

The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico-an ESE-15-one and an ESE-16 one-with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class.

Comparison of primordial germ cell differences at different developmental time points in chickens.

Recently, the application in the field of germplasm resource conservation has become an important application of primordial germ cells (PGCs). However, due to the lack of deep understanding of the biological characteristics of PGCs at different time points, there is no systematic scheme for the selection of PGCs at which time points in practical application, which affects the practical application effect of PGCs. This study aims to clarify the differences in PGCs during development. Here, migration experiment, EdU proliferation assay and cell apoptosis assay were conducted to compare the differences in the migration ability, the proliferation ability and the recovery efficiency among female and male PGCs at E3.5, E4.5, and E5.5, which were explained by the following transcriptome sequencing analysis. We found that there were larger differences between female and male PGCs at different embryonic ages, while smaller differences between female and male PGCs at the same embryonic age. Further comparison showed that the cell migration ability of female and male PGCs decreased gradually during development, so female and male PGCs at E3.5 are more suitable for in vitro allotransplantation. At the same time, the proliferation ability of PGCs gradually decreased during development, and cell adhesion and extracellular matrix communication were weakened, indicating that female and male PGCs of E3.5 are more suitable for in vitro long-term culture cell line establishment. Interestingly, female and male PGCs at E5.5 showed strong DNA damage repair ability, thus more suitable for in vitro long-term cryopreservation. This study provides a theoretical basis for systematically selecting PGCs at suitable developmental time points as cell materials for efficient utilization by analyzing the characteristics of female and male PGCs at different developmental time points based on transcriptome.

The EV antibody database: An interactive database of curated antibodies for extracellular vesicle and nanoparticle research

Antibodies are critical tools for research into extracellular vesicles (EVs) and other extracellular nanoparticles (ENPs), where they can be used for their identification, characterization, and isolation. However, the lack of a centralized antibody platform where researchers can share validation results thus minimizing wasted personnel time and reagents, has been a significant obstacle. Moreover, because the performance of antibodies varies among assay types and conditions, detailed information on assay variables and protocols is also of value. To facilitate sharing of results on antibodies that are relevant to EV/ENP research, the EV Antibody Database has been developed by the investigators of the Extracellular RNA Communication Consortium (ERCC). Hosted by the ExRNA Portal (https://exrna.org/resources/evabdb/), this interactive database aggregates and shares results from antibodies that have been tested by research groups in the EV/ENP field. Currently, the EV Antibody Database includes modules for antibodies tested for western Blot, EV Flow Cytometry, and EV Sandwich Assays, and holds 110 records contributed by 6 laboratories from the ERCC. Detailed information on antibody sources, assay conditions, and results is provided, including negative results. We encourage ongoing expert input and community feedback to enhance the database's utility, making it a valuable resource for comprehensive validation data on antibodies and protocols in EV biology.

Impacts of tissue context on extracellular vesicles-mediated cancer-host cell communications.

Tumor tissue is densely packed with cancer cells, non-cancerous cells, and ECM, forming functional structures. Cancer cells transfer extracellular vesicles (EVs) to modify surrounding normal cells into cancer-promoting cells, establishing a tumor-favorable environment together with other signaling molecules and structural components. Such tissue environments largely affect cancer cell properties, and so as EV-mediated cellular communications within tumor tissue. However, current research on EVs focuses on functional analysis of vesicles isolated from the liquid phase, including cell culture supernatants and blood draws, 2D-cultured cell assays, or systemic analyses on animal models for biodistribution. Therefore, we have a limited understanding of local EV transfer within tumor tissues. In this review, we discuss the need to study EVs in a physiological tissue context by summarizing the current findings on the impacts of tumor tissue environment on cancer EV properties and transfer and the techniques required for the analysis. Tumor tissue environment is likely to alter EV properties, pose physical barriers, interactions, and interstitial flows for the dynamics, and introduce varieties in the cell types taken up. Utilizing physiological experimental settings and spatial analyses, we need to tackle the remaining questions on physiological EV-mediated cancer-host cell interactions. Understanding cancer EV-mediated cellular communications in physiological tumor tissues will lead to developing interaction-targeting therapies and provide insight into EV-mediated non-cancerous cells and interspecies interactions.

Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.

Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.

Tumor-derived apoptotic extracellular vesicle-mediated intercellular communication promotes metastasis and stemness of lung adenocarcinoma

Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) are inevitably phagocytosed by live tumor cells, promoting tumor heterogeneity. Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence. Herein, we conducted a series of in vivo and in vitro experiments, and we report that tumor-derived apoEVs promoted lung adenocarcinoma (LUAD) metastasis, self-renewal and chemoresistance. Mechanistically, we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2. In addition, we found that ALDH1A1, which was transported by apoEVs, activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells. Furthermore, targeting apoEVs-ALDH1A1 significantly abrogated these effects. Collectively, our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations, and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.

APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Transcriptomic Signatures of Neuronally Derived Extracellular Vesicles Reveal the Presence of Olfactory Receptors in Clinical Samples from Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) is defined as an injury to the brain by external forces which can lead to cellular damage and the disruption of normal central nervous system functions. The recently approved blood-based biomarkers GFAP and UCH-L1 can only detect injuries which are detectable on CT, and are not sensitive enough to diagnose milder injuries or concussion. Exosomes are small microvesicles which are released from the cell as a part of extracellular communication in normal as well as diseased states. The objective of this study was to identify the messenger RNA content of the exosomes released by injured neurons to identify new potential blood-based biomarkers for TBI. Human severe traumatic brain injury samples were used for this study. RNA was isolated from neuronal exosomes and total transcriptomic sequencing was performed. RNA sequencing data from neuronal exosomes isolated from serum showed mRNA transcripts of several neuronal genes. In particular, mRNAs of several olfactory receptor genes were present at elevated concentrations in the neuronal exosomes. Some of these genes were OR10A6, OR14A2, OR6F1, OR1B1, and OR1L1. RNA sequencing data from exosomes isolated from CSF showed a similar elevation of these olfactory receptors. We further validated the expression of these samples in serum samples of mild TBI patients, and a similar up-regulation of these olfactory receptors was observed. The data from these experiments suggest that damage to the neurons in the olfactory neuroepithelium as well as in the brain following a TBI may cause the release of mRNA from these receptors in the exosomes. Hence, olfactory receptors can be further explored as biomarkers for the diagnosis of TBI.