Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Humans ; Paxillin/metabolism* ; Protein-Lysine 6-Oxidase/metabolism* ; Carcinoma, Squamous Cell/pathology* ; Epithelial-Mesenchymal Transition ; Integrin alpha2beta1/metabolism* ; Mouth Neoplasms/pathology* ; Collagen/metabolism* ; Fibroblasts ; Extracellular Vesicles/metabolism* ; Cell Line, Tumor ; Tumor Microenvironment

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.
Mice ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Mice, Nude ; Epithelial-Mesenchymal Transition ; Thyroid Neoplasms/pathology* ; Extracellular Vesicles/pathology* ; Mesenchymal Stem Cells ; Transcription Factors, TFIII/metabolism* ; Neoplastic Stem Cells/pathology*

Sepsis is a life-threatening organ dysfunction caused by infection that lead to dysregulation of the host response. Sepsis and septic shock with a high mortality threaten human health at present, which are important medical and health problems. Early diagnosis and treatment decision-making for sepsis and septic shock still need to be improved. Exosomes are extracellular vesicles with a diameter of 30-150 nm formed by the fusion of multi-vesicle bodies and cell membranes. Exosomes can effectively transport a variety of bioactive substances such as proteins, lipids, RNA, DNA, and participate in the regulation of inflammatory response, immune response, infection and other pathophysiological processes. In recent years, exosomes have become one of the important methods for the diagnosis and treatment of systemic inflammatory diseases. This article will focus on the basic and clinical research of sepsis, and focus on the research progress of exosomes in the diagnosis and targeted therapy of sepsis.
Humans ; Shock, Septic/therapy* ; Exosomes/metabolism* ; Sepsis/therapy* ; Extracellular Vesicles/metabolism* ; RNA/metabolism*

Severe muscle injury is hard to heal and always results in a poor prognosis. Recent studies found that extracellular vesicle-based therapy has promising prospects for regeneration medicine, however, whether extracellular vesicles have therapeutic effects on severe muscle injury is still unknown. Herein, we extracted apoptotic extracellular vesicles derived from mesenchymal stem cells (MSCs-ApoEVs) to treat cardiotoxin induced tibialis anterior (TA) injury and found that MSCs-ApoEVs promoted muscles regeneration and increased the proportion of multinucleated cells. Besides that, we also found that apoptosis was synchronized during myoblasts fusion and MSCs-ApoEVs promoted the apoptosis ratio as well as the fusion index of myoblasts. Furthermore, we revealed that MSCs-ApoEVs increased the relative level of creatine during myoblasts fusion, which was released via activated Pannexin 1 channel. Moreover, we also found that activated Pannexin 1 channel was highly expressed on the membrane of myoblasts-derived ApoEVs (Myo-ApoEVs) instead of apoptotic myoblasts, and creatine was the pivotal metabolite involved in myoblasts fusion. Collectively, our findings firstly revealed that MSCs-ApoEVs can promote muscle regeneration and elucidated that the new function of ApoEVs as passing inter-cell messages through releasing metabolites from activated Pannexin 1 channel, which will provide new evidence for extracellular vesicles-based therapy as well as improving the understanding of new functions of extracellular vesicles.
Creatine/metabolism* ; Extracellular Vesicles ; Muscle, Skeletal/metabolism* ; Myoblasts/metabolism* ; Regeneration ; Connexins/metabolism*

Dental stem cells (DSCs), an important source of mesenchymal stem cells (MSCs), can be easily obtained by minimally invasive procedures and have been used for the treatment of various diseases. Classic paradigm attributed the mechanism of their therapeutic action to direct cell differentiation after targeted migration, while contemporary insights into indirect paracrine effect opened new avenues for the mystery of their actual low engraftment and differentiation ability in vivo. As critical paracrine effectors, DSC-derived extracellular vesicles (DSC-EVs) are being increasingly linked to the positive effects of DSCs by an evolving body of in vivo studies. Carrying bioactive contents and presenting therapeutic potential in certain diseases, DSC-EVs have been introduced as promising treatments. Here, we systematically review the latest in vivo evidence that supports the therapeutic effects of DSC-EVs with mechanistic studies. In addition, current challenges and future directions for the clinical translation of DSC-EVs are also highlighted to call for more attentions to the (I) distinguishing features of DSC-EVs compared with other types of MSC-EVs, (II) heterogeneity among different subtypes of DSC-derived EVs, (III) action modes of DSC-EVs, (IV) standardization for eligible DSC-EVs and (V) safety guarantee for the clinical application of DSC-EVs. The present review would provide valuable insights into the emerging opportunities of DSC-EVs in future clinical applications.
Cell Differentiation ; Extracellular Vesicles/metabolism* ; Mesenchymal Stem Cell Transplantation/methods* ; Mesenchymal Stem Cells/metabolism*

Extracellular vesicles (EVs) are anuclear particles composed of lipid bilayers that contain nucleic acids, proteins, lipids, and organelles. EVs act as an important mediator of cell-to-cell communication by transmitting biological signals or components, including lipids, proteins, messenger RNAs, DNA, microRNAs, organelles, etc, to nearby or distant target cells to activate and regulate the function and phenotype of target cells. Under physiological conditions, EVs play an essential role in maintaining the homeostasis of the pulmonary milieu but they can also be involved in promoting the pathogenesis and progression of various respiratory diseases including chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, idiopathic pulmonary fibrosis (IPF), and pulmonary artery hypertension. In addition, in multiple preclinical studies, EVs derived from mesenchymal stem cells (EVs) have shown promising therapeutic effects on reducing and repairing lung injuries. Furthermore, in recent years, researchers have explored different methods for modifying EVs or enhancing EVs-mediated drug delivery to produce more targeted and beneficial effects. This article will review the characteristics and biogenesis of EVs and their role in lung homeostasis and various acute and chronic lung diseases and the potential therapeutic application of EVs in the field of clinical medicine.
DNA/metabolism* ; Extracellular Vesicles/metabolism* ; Humans ; Lipid Bilayers/metabolism* ; Lung Diseases/therapy* ; Lung Injury/metabolism* ; MicroRNAs/metabolism* ; Proteins/metabolism* ; Respiratory Distress Syndrome

Extracellular vesicles (EVs), also known as membrane vesicles, are vesicular bodies secreted by eukaryotic cells and bacteria. EVs can carry proteins, DNA, RNA, and various metabolites for the exchange and transmission of substances between cells. They play contents-dependent physiological functions, such as delivering nutrients, participating in immune response, and treating cancers. Currently, most studies focus on the exploration of vesicles secreted by eukaryotic cells and gram-negative bacteria, while few studies focus on gram-positive bacteria. This review summarized the production, content composition, physiological function, and engineering of EVs secreted by gram-positive bacteria, and prospected future perspectives in this area.
Bacteria/metabolism* ; Extracellular Vesicles/metabolism* ; Gram-Negative Bacteria ; Gram-Positive Bacteria/metabolism* ; Proteins/metabolism*

Extracellular vesicles (EVs) are membrane-bound particles actively released by cells. In prokaryotes and eukaryotes, EVs are effective bridges for communication between cells. EVs carry biological macromolecules, including proteins, lipids and nucleic acid, which affects different physiological functions of parent cells and recipient cells. Among them, the microRNA carried by EVs is the most reported and plays an important role in physiological function of organisms. During the development of follicles, only a few follicles can fully develop and ovulate, whereas most of them undergo atresia at different stages of development. In the whole process of follicular development, the changes at each stage and the regulation mechanism of follicular atresia are not completely understood. In this paper, we introduced the types, characteristics, isolation methods and uses of EVs, and emphasized how microRNA carried by EVs in follicular fluid regulated follicular atresia from the aspects of different cytokines and hormones. Additionally, the application prospect of microRNA carried by EVs in follicular fluid in reproductive regulation and reproductive disease diagnosis was discussed. This paper is significant for studying the regulation of follicular development and the effective utilization of oocytes.
Animals ; Extracellular Vesicles/metabolism* ; Female ; Follicular Atresia ; Follicular Fluid ; MicroRNAs/metabolism* ; Oocytes

Multiple myeloma (MM) is a common hematologic tumor characterized by malignant proliferation of clonal plasma cells, the exact pathogenesis of which is not yet fully understood. The extracellular vesicles (EV) are structures released by cells into their surroundings that do not have a functional nucleus and can communicate between cells or deliver biologically active proteins and nucleic acids to target cells. EV play an important role in the interaction between myeloma cells and the bone marrow microenvironment, and they can promote MM progression. In this paper, we summarize the recent research progress in the mechanism of action of EV on MM in order to provide inspiration for exploring new strategies for MM treatment and prognostic stratification.
Bone Marrow/metabolism* ; Extracellular Vesicles/pathology* ; Hematologic Neoplasms/metabolism* ; Humans ; Multiple Myeloma/pathology* ; Nucleic Acids/metabolism* ; Tumor Microenvironment

Traumatic brain injury (TBI) contributes to the key causative elements of neurological deficits. However, no effective therapeutics have been developed yet. In our previous work, extracellular vesicles (EVs) secreted by stem cells from human exfoliated deciduous teeth (SHED) offered new insights as potential strategies for functional recovery of TBI. The current study aims to elucidate the mechanism of action, providing novel therapeutic targets for future clinical interventions. With the miRNA array performed and Real-time PCR validated, we revealed the crucial function of miR-330-5p transferred by SHED-derived EVs (SHED-EVs) in regulating microglia, the critical immune modulator in central nervous system. MiR-330-5p targeted Ehmt2 and mediated the transcription of CXCL14 to promote M2 microglia polarization and inhibit M1 polarization. Identified in our in vivo data, SHED-EVs and their effector miR-330-5p alleviated the secretion of inflammatory cytokines and resumed the motor functional recovery of TBI rats. In summary, by transferring miR-330-5p, SHED-EVs favored anti-inflammatory microglia polarization through Ehmt2 mediated CXCL14 transcription in treating traumatic brain injury.
Animals ; Brain Injuries, Traumatic/therapy* ; Chemokines, CXC/metabolism* ; Extracellular Vesicles/metabolism* ; Histocompatibility Antigens/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Humans ; MicroRNAs/metabolism* ; Microglia/metabolism* ; Rats ; Stem Cells/metabolism*