Role In Intercellular Signaling Research Articles

Role of Endometrial Extracellular Vesicles in Mediating Cell-to-Cell Communication in the Uterus: A Review.

There are several critical events that occur in the uterus during early pregnancy which are necessary for the establishment and maintenance of pregnancy. These events include blastocyst implantation, uterine decidualization, uterine neoangiogenesis, differentiation of trophoblast stem cells into different trophoblast cell lineages, and formation of a placenta. These processes involve several different cell types within the pregnant uterus. Communication between these cell types must be intricately coordinated for successful embryo implantation and the formation of a functional maternal-fetal interface in the placenta. Understanding how this intricate coordination transpires has been a focus of researchers in the field for many years. It has long been understood that maternal endometrial tissue plays a key role in intercellular signaling during early pregnancy, sending signals to nearby tissues in a paracrine manner. Recently, insights have been obtained into the mechanisms by which these signaling events occur. Notably, the endometrium has been shown to secrete extracellular vesicles (EVs) that contain crucial cargo (proteins, lipids, RNA, miRNA) that are taken up by recipient cells to initiate a response leading to the occurrence of critical events during implantation and placentation. In this review, we aim to summarize the role that endometrium-derived EVs play in mediating cell-to-cell communications within the pregnant uterus to orchestrate the events that must occur to establish and maintain pregnancy. We will also discuss how aberrant endometrial EV signaling may lead to pathophysiological conditions, such as endometriosis and infertility.

Environmental and Lifestyle Cancer Risk Factors: Shaping Extracellular Vesicle OncomiRs and Paving the Path to Cancer Development.

Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m2 (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future.

Distribution of Signal Peptides in Microvesicles from Activated Macrophage Cells.

Extracellular vesicles, such as microvesicles (LEV) and exosomes (SEV), play an important role in intercellular signaling by encapsulating functional molecules and delivering them to specific cells. Recent studies showed that signal peptides (SPs), which are derived from sequences at the N-terminal of newly synthesized proteins, exhibited biological activity in the extracellular fluid. We previously reported that SPs were secreted into the extracellular fluid via SEV; however, it remains unclear whether the release of SPs occurs via LEV. In the present study, we demonstrated that SP fragments from human placental secreted alkaline phosphatase (SEAP) were present in LEV as well as SEV released from RAW-Blue cells, which stably express an NF-κB-inducible SEAP reporter. When RAW-Blue cells were treated with LPS at 0-10,000 ng/mL, SEAP SP fragments per particle were more abundant in LEV than in SEV, with fragments in LEV and SEV reaching a maximum at 1000 and 100 ng/mL, respectively. The content of SEAP SP fragments in LEV from IFNγ-stimulated RAW-Blue cells was higher than those from TNFα-stimulated cells, whereas that in SEV from TNFα-stimulated RAW-Blue cells was higher than those from IFNγ-stimulated cells. Moreover, the content of SEAP SP fragments in LEV and SEV decreased in the presence of W13, a calmodulin inhibitor. Collectively, these results indicate that the transportation of SP fragments to extracellular vesicles was changed by cellular activation, and calmodulin was involved in their transportation to LEV and SEV.

Pannexin-1 Modulates Inhibitory Transmission and Hippocampal Synaptic Plasticity.

Pannexin-1 (Panx1) hemichannel is a non-selective transmembrane channel that may play important roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Although recent evidence shows that the Panx1 hemichannel is involved in controlling excitatory synaptic transmission, the role of Panx1 in inhibitory transmission remains unknown. Here, we studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. We reported that blockage of the Panx1 hemichannel with the mimetic peptide 10Panx1 increases the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which results in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Our finding provides important insight unveiling that Panx1 can strongly influence the overall neuronal excitability and play a key role in shaping synaptic changes affecting the amplitude and direction of plasticity, as well as learning and memory processes.

The emerging role of extracellular vesicles as communicators between adipose tissue and pathologic lungs with a special focus on asthma.

Extracellular vesicles (EVs) gain increasing attention due to their (patho-)physiological role in intercellular signaling, specifically in the communication between distant organs. Recent studies highlight a connection between the adipose tissue (AT) and the lung via (immuno-)modulatory EVs in disorders such as obesity-associated asthma and lung cancer-associated cachexia. Although lung cancer-derived EVs induce lipolysis and myotube atrophy in vivo, pathogenic effects were also reported in the opposite direction with the involvement of AT-derived EVs in cancer-promoting responses and potentially in asthma development. In contrast, the majority of studies on AT-derived EVs demonstrate their protective influence on the asthmatic lung. Beneficial effects, such as induction of anti-inflammatory pathways in vitro and in ovalbumin (OVA)-induced asthma mouse models, were particularly conveyed by EVs enriched from AT-derived mesenchymal stem/stromal cells (AT-MSCs), which therefore pose an interesting subject in possible future therapeutic applications. Likewise, AT-MSC-derived EVs exerted beneficial effects in several other pulmonary abnormalities, such as different types of lung injury or pathological changes related to chronic obstructive pulmonary disease. These contradictory findings highlight the need for extensive research to widen the understanding of the role of EVs in the development of diseases and interconnectivity between organs.

The Role of Intercellular Signaling in the Regulation of Bacterial Adaptive Proliferation.

Bacterial adaptation is regulated at the population level with the involvement of intercellular communication (quorum sensing). When the population density is insufficient for adaptation under starvation, bacteria can adjust it to a quorum level through cell divisions at the expense of endogenous resources. This phenomenon has been described for the phytopathogenic bacterium Pectobacterium atrosepticum (Pba), and it is called, in our study, adaptive proliferation. An important attribute of adaptive proliferation is its timely termination, which is necessary to prevent the waste of endogenous resources when the required level of population density is achieved. However, metabolites that provide the termination of adaptive proliferation remained unidentified. We tested the hypothesis of whether quorum sensing-related autoinducers prime the termination of adaptive proliferation and assessed whether adaptive proliferation is a common phenomenon in the bacterial world. We showed that both known Pba quorum sensing-related autoinducers act synergistically and mutually compensatory to provide the timely termination of adaptive proliferation and formation of cross-protection. We also demonstrated that adaptive proliferation is implemented by bacteria of many genera and that bacteria with similar quorum sensing-related autoinducers have similar signaling backgrounds that prime the termination of adaptive proliferation, enabling the collaborative regulation of this adaptive program in multispecies communities.

Efficient Small Extracellular Vesicles (EV) Isolation Method and Evaluation of EV-Associated DNA Role in Cell–Cell Communication in Cancer

Simple SummarySmall extracellular vesicles (sEVs) released by all cell types function as a mediator in intercellular communication that can promote cell division and survival to remodel the tumor microenvironment to develop tumor invasion and metastasis. Even though dsDNA baggage is associated with all small EV populations, the functional role of EV-DNA in cancer remains poorly understood. This is due to a lack of methods allowing the efficient separation of small EVs (sEVs) from other non-sEV components. The main aim of our study was to develop an efficient sEV isolation method along with EV-associated DNA (EV-DNA) monitoring tool to evaluate the role of EV-DNA as a mediator of cell–cell communication in cancer. Our detailed small EV-DNA characterization confirmed that isolated sEVs using the TSU method (Tangential flow filtration + Size exclusion chromatography + Ultrafiltration) are free from contaminants such as cell-free and apoptotic bodies DNA, making TSU ideal for performing EV-DNA functional studies. Next, we revealed the exact EV-DNA distribution in the recipient cells using 3D image analysis and the association of EV-DNA with key cellular proteins, which may have an essential role in cancer. In the leukemia model, EV-DNA isolated from leukemia cell lines associated with mesenchymal stromal cells (MSCs), a crucial factor in the bone marrow (BM) microenvironment.Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this work, using controlled culture conditions, we enriched the reproducible separation of sEVs from free-circulated components by combining tangential flow filtration, size-exclusion chromatography, and ultrafiltration (TSU). EV-enriched fractions (F2 and F3) obtained using TSU also contained more dsDNA derived from the host genome and mitochondria, predominantly localized inside the vesicles. Three-dimensional reconstruction of high-resolution imaging showed that the recipient cell membrane barrier restricts a portion of EV-DNA. Simultaneously, the remaining EV-DNA overcomes it and enters the cytoplasm and nucleus. In the cytoplasm, EV-DNA associates with dsDNA-inflammatory sensors (cGAS/STING) and endosomal proteins (Rab5/Rab7). Relevant to cancer, we found that EV-DNA isolated from leukemia cell lines communicates with mesenchymal stromal cells (MSCs), a critical component in the BM microenvironment. Furthermore, we illustrated the arrangement of sEVs and EV-DNA at a single vesicle level using super-resolution microscopy. Altogether, employing TSU isolation, we demonstrated EV-DNA distribution and a tool to evaluate the exact EV-DNA role of cell–cell communication in cancer.

Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS) is a serious disease whose cause has yet to be identified. Objective markers of the disease are also not well understood and would serve as important tools in diagnosis and management. One potential biomarker or transmitter of immune signals in ME/CFS is the extracellular vesicle (EV) compartment. These small, membrane bound particles have been shown to play a key role in intercellular signaling. Our laboratory has focused on methods of detection of EVS in clinical samples. In this study we explored whether the prevalence of EVs in the plasma of participants with mild or severe ME/CFS differed from the plasma of healthy control participants. By staining for multiple cell surface molecules, plasma EVs could be fingerprinted as to their cell of origin. Our study revealed a significant correlation between severe ME/CSF and levels of EVs bearing the B cell marker CD19 and the platelet marker CD41a, though these changes were not significant after correction for multiple comparisons. These findings point to potential dysregulation of B cell and platelet activation or homeostasis in ME/CFS, which warrants validation in a replication cohort and further exploration of potential mechanisms underlying the association.

Open Problems in Extracellular RNA Data Analysis: Insights From an ERCC Online Workshop.

We now know RNA can survive the harsh environment of biofluids when encapsulated in vesicles or by associating with lipoproteins or RNA binding proteins. These extracellular RNA (exRNA) play a role in intercellular signaling, serve as biomarkers of disease, and form the basis of new strategies for disease treatment. The Extracellular RNA Communication Consortium (ERCC) hosted a two-day online workshop (April 19–20, 2021) on the unique challenges of exRNA data analysis. The goal was to foster an open dialog about best practices and discuss open problems in the field, focusing initially on small exRNA sequencing data. Video recordings of workshop presentations and discussions are available (https://exRNA.org/exRNAdata2021-videos/). There were three target audiences: experimentalists who generate exRNA sequencing data, computational and data scientists who work with those groups to analyze their data, and experimental and data scientists new to the field. Here we summarize issues explored during the workshop, including progress on an effort to develop an exRNA data analysis challenge to engage the community in solving some of these open problems.

Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods

Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods

Discovery and Development of Promiscuous O-Glycan Hydrolases for Removal of Intact Sialyl T-Antigen.

Mucin-type O-glycosylation (O-glycosylation) is a common post-translational modification that confers distinct biophysical properties to proteins and plays crucial roles in intercellular signaling. Yet, despite the importance of O-glycans, relatively few tools exist for their analysis and modification. In particular, there is a need for enzymes that can cleave the wide range of O-glycan structures found on protein surfaces, to facilitate glycan profiling and editing. Through functional metagenomic screening of the human gut microbiome, we discovered endo-O-glycan hydrolases from CAZy family GH101 that are capable of slowly cleaving the intact sialyl T-antigen trisaccharide (a ubiquitous O-glycan structure in humans) in addition to their primary activity against the T-antigen disaccharide. We then further explored this sequence space through phylogenetic profiling and analysis of representative enzymes, revealing large differences in the levels of this promiscuous activity between enzymes within the family. Through structural and sequence analysis, we identified active site residues that modulate specificity. Through subsequent rational protein engineering, we improved the activity of an enzyme identified by phylogenetic profiling sufficiently that substantial removal of the intact sialyl T-antigen from proteins could be readily achieved. Our best sialyl T-antigen hydrolase mutant, SpGH101 Q868G, is further shown to function on a number of proteins, tissues, and cells. Access to this enzyme opens up improved methodologies for unraveling the glycan code.

Identification of PDGFR\u03b1-positive interstitial cells in the distal segment of the murine vas deferens

Platelet-derived growth factor receptor-α (PDGFRα)-positive interstitial cells (ICs) are widely distributed in various organs and may be involved in the motility of various tubular organs. We, for the first time, aimed to investigate the distribution, immunohistochemical characteristics, and ultrastructure of PDGFRα-positive ICs in murine vas deferens, using confocal laser scanning microscopy, transmission electron microscopy (TEM), and immuno-electron microscopy (immuno-EM). For immunofluorescence, we used antibodies against PDGFRα and other markers of ICs. PDGFRα-positive ICs were distributed widely in the lamina propria, smooth muscles, and serosal layers. Although most PDGFRα-positive ICs labeled CD34, they did not label CD34 in the subepithelial layers. Additionally, PDGFRα-positive ICs were in close proximity to each other, as also to the surrounding cells. TEM and immuno-EM findings revealed that PDGFRα-positive ICs established close physical interactions with adjacent ICs. Extracellular vesicles were also detected around the PDGFRα-positive ICs. Our morphological findings suggest that PDGFRα-positive ICs may have several subpopulations, which can play an important role in intercellular signaling via direct contact with the IC network and the extracellular vesicles in the murine vas deferens. Further investigation on PDGFRα-positive ICs in the vas deferens may lead to understanding the vas deferens mortility.

Distinct profile of CD34+ cells and plasma-derived extracellular vesicles from triple-negative patients with Myelofibrosis reveals potential markers of aggressive disease

BackgroundMyelofibrosis (MF) is a clonal disorder of hemopoietic stem/progenitor cells (HSPCs) with high prevalence in elderly patients and mutations in three driver genes (JAK2, MPL, or CALR). Around 10–15% of patients are triple-negative (TN) for the three driver mutations and display significantly worse survival. Circulating extracellular vesicles (EVs) play a role in intercellular signaling and are increased in inflammation and cancer. To identify a biomolecular signature of TN patients, we comparatively evaluated the circulating HSPCs and their functional interplay with the microenvironment focusing on EV analysis.MethodsPeripheral blood was collected from MF patients (n = 29; JAK2V617F mutation, n = 23; TN, n = 6) and healthy donors (HD, n = 10). Immunomagnetically isolated CD34+ cells were characterized by gene expression profiling analysis (GEP), survival, migration, and clonogenic ability. EVs were purified from platelet-poor plasma by ultracentrifugation, quantified using the Nanosight technology and phenotypically characterized by flow cytometry together with microRNA expression. Migration and survival of CD34+ cells from patients were also analyzed after in vitro treatments with selected inflammatory factors, i.e. (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, IL6) or after co-culture with EVs from MF patients/HD.ResultsThe absolute numbers of circulating CD34+ cells were massively increased in TN patients. We found that TN CD34+ cells show in vitro defective functions and are unresponsive to the inflammatory microenvironment. Of note, the plasma levels of crucial inflammatory cytokines are mostly within the normal range in TN patients. Compared to JAK2V617F-mutated patients, the GEP of TN CD34+ cells revealed distinct signatures in key pathways such as survival, cell adhesion, and inflammation. Importantly, we observed the presence of mitochondrial components within plasma EVs and a distinct phenotype in TN-derived EVs compared to the JAK2V617F-mutated MF patients and HD counterparts. Notably, TN EVs promoted the survival of TN CD34+ cells. Along with a specific microRNA signature, the circulating EVs from TN patients are enriched with miR-361-5p.ConclusionsDistinct EV-driven signals from the microenvironment are capable to promote the TN malignant hemopoiesis and their further investigation paves the way toward novel therapeutic approaches for rare MF.

135 Purification and characterization of human placental-derived exosomes from maternal serum using size exclusion chromatography

Exosomes are extracellular vesicles that contain a diverse array of signaling molecules and have a role in intercellular signaling. Placental tissues release exosomes that have been identified in maternal blood. The purpose of this study is to evaluate a method of exosome isolation using size-exclusion chromatography (SEC) columns to purify exosomes in a reproducible, time-efficient manner, enabling analysis of the biological activity of placental-derived exosomes (PDE). Stored samples from a previous prospective longitudinal study of women with uncomplicated pregnancies were used. Exosomes were isolated from third trimester and postpartum (24–48h after delivery) serum samples using SEC (Fig.1). We then confirmed the presence of exosomes using Nanodrop spectrophotometry (Abs 280 nm), Nanoparticle Tracking Analysis (NTA), and Western blot analysis for protein quantification, size determination and presence of syncytiotrophoblast specific marker Anti-Placental Alkaline Phosphatase (PLAP), respectively. After SEC of maternal serum (n=10), NTA revealed particle size to be 60 and 70 nm, on average. NTA and Nanodrop A280 of SEC fractions revealed a distinct exosome peak in both particle concentration and total protein content, indicating the presence of exosomes that could be further processed and analyzed. Western blot analysis of the proteins identified presence of syncytiotrophoblast specific marker PLAP in all samples (Fig.1). PDEs were present in maternal serum 24–48 hours after delivery. Although there were significant differences in the concentrations of exosomes in maternal serum from third trimester versus postpartum within individual patients, there was no consistent correlation of concentration difference between individual patients (Fig.2). SEC is a simple and reproducible technique to purify placental-derived exosomes from maternal serum. Placental exosomes are present in the serum of recently postpartum patients. These findings will facilitate further studies in the biological functions of placental-derived exosomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

ROS-induced dramatic lipid changes in Arabidopsis

ABSTRACT Objectives: The beneficial role of ROS was probably in promoting intercellular communication by modifying membrane constituents [Liang D. A salutary role of reactive oxygen species in intercellular tunnel-mediated communication. Front Cell Dev Biol. 2018;6:2]. We investigated how the membrane lipids were responding to ROS and ROS inhibitors. Methods: To examine how ROS affected the lipid profiles, we used thin-layer chromatography to characterize lipid profiles in Arabidopsis plants. Then, the confocal microscopy imaging was used to confirm the change of membrane lipid in a plasma membrane marker line exposed to ROS and ROS inhibitors. Results: We found the relative contents of most lipids in H2O2-treated Arabidopsis plants were increased in roots, rather than in shoots. The increased fluorescent signal of membrane marker induced by H2O2 was mainly enriched in the conductive parts of roots. Several ROS inhibitors also strongly affected the lipid profiles. Among them, diethyldithiocarbamate (DDC) can progressively change the lipid profiles with treatment going on. Membrane marker signal was mainly accumulated in the root tips and epidermal cells after treatment by DDC. Discussion: H2O2 may enhance intercellular communication by inducing different lipid species in the conductive parts of roots. The lipid profiles were widely responding to various ROS reagents and might play a role in intercellular signaling.

Sensory Cilia Act as a Specialized Venue for Regulated Extracellular Vesicle Biogenesis and Signaling

Extracellular vesicles play major roles in intercellular signaling, yet fundamental aspects of their biology remain poorly understood. Ciliary EV shedding is evolutionary conserved. Here we use super resolution, real time imaging of fluorescent-protein tagged EV cargo combined with in vivo bioassays to study ciliary EVs in C. elegans. We find that neuronal sensory cilia shed the TRP polycystin-2 channel PKD-2::GFP-carrying EVs from two distinct sites - the ciliary tip and the ciliary base. Ciliary tip shedding requires distal ciliary enrichment of PKD-2 by the myristoylated coiled-coil protein CIL-7. Kinesin-3 KLP-6 and intraflagellar transport (IFT) kinesin-2 motors are also required for ciliary tip EV shedding. Blocking ciliary tip shedding results in excessive EV shedding from the base. Finally, we demonstrate that C. elegans male ciliated neurons modulate EV cargo composition in response to sensory stimulation by hermaphrodite mating partners. Overall, our study indicates that the cilium and its trafficking machinery act as a specialized venue for regulated EV biogenesis and signaling.

The Biomarker Potential of miRNAs in Myotonic Dystrophy Type I.

MicroRNAs (miRNAs) are mostly known for their gene regulation properties, but they also play an important role in intercellular signaling. This means that they can be found in bodily fluids, giving them excellent biomarker potential. Myotonic Dystrophy type I (DM1) is the most frequent autosomal dominant muscle dystrophy in adults, with an estimated prevalence of 1:8000. DM1 symptoms include muscle weakness, myotonia, respiratory failure, cardiac conduction defects, cataracts, and endocrine disturbances. Patients display heterogeneity in both age of onset and disease manifestation. No treatment or cure currently exists for DM1, which shows the necessity for a biomarker that can predict disease progression, providing the opportunity to implement preventative measures before symptoms arise. In the past two decades, extensive research has been conducted in the miRNA expression profiles of DM1 patients and their biomarker potential. Here we review the current state of the field with a tissue-specific focus, given the multi-systemic nature of DM1 and the intracellular signaling role of miRNAs.

Mesenchymal stem cells derived extracellular vesicles ameliorate cortical cerebellar changes-induced by aspartame in rats, Histological and immunohistochemical study.

Background: Exosomes are endogenous nanovesicles that cooperate key roles in intercellular signaling by bearing functional genetic information and proteins between cells. Exosomes speedily cross the blood-brain barrier and have indicated as therapeutic approach vehicles that have the potential to specifically deliver molecules to the central nervous system (CNS). Aspartame (ASP) is applied in many products. ASP has been interconnected to cause neurological and behavioral changes such as headache, insomnia, and seizures.Aim: Aim of this study was to determine the potential role of exosomes on cerebellar changes caused by aspartame (ASP).Materials and Methods: Thirty five adult male albin0 rats were divided into three gr0ups. The first group served as the c0ntrol group. In the second group, the rats were given ASP orally at a d0se of 250 mg/kg/day for 6 weeks. In the third group, the rats were given ASP as group II plus exosomes in a d0se of 100 mg/kg intravenously/twice per week. At the end of the 6th week of the experiment cerebellar specimens were appr0priated for histological and immuno-histochemical studies.Results: In the ASP‑treated group, dis0rganization of the three layers of the cerebellar c0rtex was observed. Spaces were seen between the cells. Small pykn0tic nuclei of Purkinje cells and deformed cells were also detected . Furthermore, there was a significant increase (p ≤ 0.01) of GFAP, COX-2 and caspase-3 immune expression compared with control group. Ex0somes in conjunction with ASP resulted in impr0vement in the organization of cellular layers of the cerebellar c0rtex with a significant decrease (p ≤ 0.01) of GFAP, COX-2 and caspase-3 immune expressi0n compared with group II.Conclusion: Exosomes ameli0rates the neuropathol0gical changes caused by aspartame on the structure of the cerebellar cortex of albin0 rats.

Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission.

G protein-coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of Gq and Gi/o GPCR activation on astroglial Ca2+ -based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while Gq GPCR activation led to cellular activation in both neurons and astrocytes, Gi/o GPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either Gq or Gi/o protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of Gq and Gi/o DREADDs in vivo increased astrocyte Ca2+ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia-neuron network operation and brain function.

Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles

In autoimmune disease body's own immune system knows healthy cells as undesired and foreign cells. Over 80 types of autoimmune diseases have been recognized. Currently, at clinical practice, treatment strategies for autoimmune disorders are based on relieving symptoms and preventing difficulties. In other words, there is no effective and useful therapy up to now. It has been well-known that mesenchymal stem cells (MSCs) possess immunomodulatory effects. This strongly suggests that MSCs might be as a novel modality for treatment of autoimmune diseases. Supporting this notion a few preclinical and clinical studies indicate that MSCs ameliorate autoimmune disorders. Interestingly, it has been found that the beneficial effects of MSCs in autoimmune disorders are not relying only on direct cell-to-cell communication but on their capability to produce a broad range of paracrine factors including growth factors, cytokines and extracellular vehicles (EVs). EVs are multi-signal messengers that play a serious role in intercellular signaling through carrying cargo such as mRNA, miRNA, and proteins. Numerous studies have shown that MSC-derived EVs are able to mimic the effects of the cell of origin on immune cells. In this review, we discuss the current studies dealing with MSC-based therapies in autoimmune diseases and provide a vision and highlight in order to introduce MSC-derived EVs as an alternative and emerging modality for autoimmune disorders.