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PubMed2025

Exosomal proteomics reveals fatty acid metabolism linked to gefitinib resistance in non-small cell lung cancer.

Exosomes play a crucial role in the transmission of drug resistance in tumors. However, the mechanism of exosomes-mediated transmission in non-small cell lung cancer (NSCLC) under gefitinib treatment remains limited. In this work, we demonstrated that exosomes derived from HCC827/GR cells (drug-resistant) enhanced the survivability of HCC827 cells (drug-sensitive) under treatment with gefitinib. A total of 157 shared upregulated proteins between exosomes and their parent cells were identified in the comparison of the gefitinib-resistant groups versus the gefitinib-sensitive groups. Notably, 69 of these shared proteins are enzymes, and many of them were enriched in pathways related to fatty acid metabolism. Among these enzymes involved in fatty acid metabolism, ACC1 exhibited the highest fold change in upregulated expression in both drug-resistant groups (exosomes and cells). Moreover, the expression of ACC1 was upregulated in gefitinib-sensitive cells after uptake of exosomes from gefitinib-resistant cells. The role of ACC1 in enhancing the survival of HCC827/GR cells under gefitinib treatment was demonstrated using an inhibitor and siRNA-mediated knockdown. Specifically, the upregulated ACC1 stabilized fatty acid oxidation and reactive oxygen species levels in HCC827/GR cells, thereby maintaining cellular metabolic homeostasis. Collectively, this work reveals the transmission of drug resistance in NSCLC via exosomes that carry the ACC1 protein.

Humans↗

PubMed2026

Effects of umbilical cord mesenchymal stem cell-derived exosomes on periodontal ligament stem cells: An exploratory study.

OBJECTIVE: To investigate whether exosomes derived from human umbilical cord mesenchymal stem cells (UCMSCs) at two osteogenic induction stages (undifferentiated and late-stage) differentially affect periodontal ligament stem cells (PDLSCs), and to explore the potential molecular basis. DESIGN: UCMSCs and PDLSCs were isolated and cultured. Exosomes were harvested from undifferentiated UCMSCs (Exo-D0) and UCMSCs after 14 days of osteogenic induction (Exo-D14). PDLSCs were treated with both exosome types. Proliferation and migration were analyzed using EdU and scratch assays, the latter under serum-free conditions. Early osteogenic differentiation was assessed by alkaline phosphatase staining and quantitative reverse transcription PCR (qRT-PCR). Differentially expressed miRNAs were identified by high-throughput sequencing and further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. RESULTS: Both exosome types promoted PDLSC migration. Exo-D0 enhanced early osteogenic differentiation, whereas Exo-D14 enhanced proliferation but reduced early osteogenic marker expression. Sequencing identified 21 differentially expressed miRNAs (13 upregulated, 8 downregulated). Bioinformatic prediction suggested that the putative target genes were enriched in Ras signal transduction, regulation of kinase activity, and focal adhesion, and further predicted significant enrichment in the MAPK, Ras, and PI3K-Akt signaling pathways, which are central to cell proliferation and osteogenic differentiation. CONCLUSIONS: Exosomes from undifferentiated and osteogenically induced UCMSCs exerted distinct effects on PDLSCs, potentially associated with differentially packaged miRNAs. These findings offer a basis for hypotheses about exosome-mediated mechanisms and support matching exosome sources to the intended therapeutic outcome as potential cell-free strategies for periodontal tissue regeneration and alveolar bone repair.

Humans↗

PubMed2005

Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive.

We previously have demonstrated the ability of primary murine bone marrow-derived DC (BM-DC), genetically modified by adenoviral infection to express FasL, to inhibit progression of established collagen-induced arthritis (CIA) following systemic delivery. Here we demonstrate that exosomes derived from genetically modified BM-DC expressing FasL are able to inhibit inflammation in a murine footpad model of delayed-type hypersensitivity (DTH). Local administration of exosomes derived from DC expressing FasL (Exo/FasL) as well as the parental DC/FasL resulted in a significant reduction in swelling in both the treated and the untreated distal paw. However, both the DC/FasL and the Exo/FasL were unable to suppress the DTH response in lpr (Fas-deficient) mice. Gene transfer of FasL to BM-DC from gld (FasL-deficient) mice resulted in restoration of the ability of DC as well as DC-derived exosomes to suppress DTH. The ability of DC-derived exosomes and DC to suppress DTH responses was antigen specific and MHC class II dependent, but class I independent. The injected exosomes were found to be internalized into CD11c(+) cells at the site of injection and in the draining popliteal lymph node. Systemic injection of exosome/FasL into mice with established CIA resulted in significant disease amelioration. These results demonstrate that both systemic and local administration of exosomes derived from FasL-expressing DC are able to suppress antigen-specific immune responses through an MHC class II-dependent pathway, resulting in effective and sustained treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. These results suggest that DC/FasL-derived exosomes could be used clinically for the treatment of inflammatory and autoimmune diseases.

Animals↗

PubMed2006

A single subunit, Dis3, is essentially responsible for yeast exosome core activity.

The conserved core of the exosome, the major eukaryotic 3' --> 5' exonuclease, contains nine subunits that form a ring similar to the phosphorolytic bacterial PNPase and archaeal exosome, as well as Dis3. Dis3 is homologous to bacterial RNase II, a hydrolytic enzyme. Previous studies have suggested that all subunits are active 3' --> 5' exoRNases. We show here that Dis3 is responsible for exosome core activity. The purified exosome core has a hydrolytic, processive and Mg(2+)-dependent activity with characteristics similar to those of recombinant Dis3. Moreover, a catalytically inactive Dis3 mutant has no exosome core activity in vitro and shows in vivo RNA degradation phenotypes similar to those resulting from exosome depletion. In contrast, mutations in Rrp41, the only subunit carrying a conserved phosphorolytic site, appear phenotypically not different from wild-type yeast. We observed that the yeast exosome ring mediates interactions with protein partners, providing an explanation for its essential function.

Adaptor Proteins, Signal Transducing↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed2003

The association of the human PM/Scl-75 autoantigen with the exosome is dependent on a newly identified N terminus.

The exosome is a complex of 3' --> 5' exoribonucleases that functions in a variety of cellular processes, all concerning the processing or degradation of RNA. Paradoxically, the previously described cDNA for the human autoantigenic exosome subunit PM/Scl-75 (Alderuccio, F., Chan, E. K., and Tan, E. M. (1991) J. Exp. Med. 173, 941-952) encodes a polypeptide that failed to interact with the exosome complex. Here, we describe the cloning of a more complete cDNA for PM/Scl-75 encoding 84 additional amino acids at its N terminus. We show that only the longer polypeptide is able to associate with the exosome complex. This interaction is most likely mediated by protein-protein interactions with two other exosome subunits, hRrp46p and hRrp41p, one of which was confirmed in a mammalian two-hybrid system. In addition we show that the putative nuclear localization signal present in the C-terminal region of PM/Scl-75 is sufficient, although not essential for nuclear localization of the protein. Moreover, the deletion of this element abrogated the nucleolar accumulation of PM/Scl-75, although its association with the exosome was not disturbed. This suggests that this basic element of PM/Scl-75 plays a role in targeting the exosome to the nucleolus.

Alternative Splicing↗

PubMed2006

[The properties of exosomes secreted by human umbilical cord blood dendritic cells and its enhancement of CTL cytotoxicity].

AIM: To investigate the properties of exosomes secreted by dendritic cells(DCs) derived from human umbilical cord blood mononuclear cells(HUBMCs) and its enhancement of CTL cytotoxicity. METHODS: The HUBMCs were separated from human umbilical cord blood(HUCB). The generation of DCs were induced for 12 days in medium containing SCF, IL-4 and GM-CSF. Tumor antigen extracted by repeated freeze-thawing were added to culture medium and cultured successively for 2 days. The DCs were collected and exosomes were separated from culture supernatant through centrifugation at 100,000 g. The exosomes-associated properties were analyzed by FCM, SDS-PAGE, transmission electron microscope(TEM) and MTT colorimetry. RESULTS: After being induced for 12 days with SCF, IL-4 and GM-CSF the number of DCs had a 10-fold increase and displayed typically morphological characteristics of DCs. FCM analysis showed that the DCs loaded with tumor antigen expressed highly MHC-I, MHC-II, CD40, CD80, CD86, CD11c and CD54. Exosomes could be separated from culture supernatant of DCs by ultracentrifugation. Mixed lymphocyte reation(MLR) and cytotoxicity assay showed that exosomes secreted by DCs could effectively stimulate T cell proliferation and enhance their cytotoxicity. CONCLUSION: A large number of DCs are obtained from UBMCs and the exosomes are secreted from them in vitro. The exosomes can present tumor antigen to T cells and enhance the cytotoxicity of CTLs.

B7-1 Antigen↗

PubMed2026

Recent advancements in exosomal content analysis: the future of liquid biopsy.

Exosomes are widely acknowledged as an essential agent that carries biomarkers for specific diseases, representing the molecular status of their parent cells and providing extremely useful diagnostic insights. They can be isolated from different body fluids and contain a range of cargo molecules, including proteins, lipids, metabolites, and nucleic acids. Recent advancements in technology have greatly accelerated exosome research. Proteomics provides protein signatures linked to many pathological conditions, enabling quick and clinically scalable diagnostic tools, whereas high-throughput RNA-sequencing can be used to perform detailed transcriptome profiling. Exosomal biomarkers are showing promising clinical results in early detection of neurological diseases, infectious and cardiovascular disorders, oncology, and other medical conditions, hence accelerating therapeutic monitoring. Despite these advances, several challenges continue to hinder clinical translation including the lack of standardized isolation protocol, variability in exosome yield and purity, biological heterogeneity, and limited large-scale clinical validation. Addressing these limitations will be critical for the successful integration of exosome-based liquid biopsy into routine clinical practice. Overall, exosomes having significant potential as diagnostic tool, represent a transformative horizon in biomedical liquid biopsy research to redefine the landscape of less-invasive diagnostics and tailored clinical applications.

Humans↗

PubMed1996

Cleavage of the transferrin receptor by human granulocytes: differential proteolysis of the exosome-bound TFR.

In contrast with other mammalian granulocytes, human granulocytes rapidly cleave the transferrin receptor (TFR) from sheep exosomes. Proteolysis of TFR from exosomes is more rapid and more extensive than that from the sheep reticulocyte cell surface itself, although little difference in cleavage is seen when immunoprecipitates or when immobilized, solubilized receptors from the two sources are compared. Circulating exosomes but not the plasma membrane fraction from seven species of immature red cells or erythropoietic cells show the presence of a peptide of approximately 18 kD recognized by an antibody to the cytoplasmic domain of the TFR. This 18 kD peptide is virtually absent from the corresponding cellular plasma membranes including human reticulocyte membranes. Taken together, the data are consistent with the conclusion that the exosomes released to the circulation from maturing red cells are the principal source of the soluble, circulating, truncated TFR. The granulocyte protease appears to be present on the cell surface and not released into the medium after short (30 min) periods of incubation at 37 degrees C. The protease is inhibited by PMSF but only at high (1 mM) concentrations. Using sheep exosome bound-TFR as substrate, human granulocytes exceed other granulocytes in their capacity to cleave TFR, suggesting that this may be a key factor for the prominent amount of circulating, soluble receptor found in human sera during periods of elevated reticulocyte levels. Human exosomes, unlike those from other species, contain little native size TFR. Truncated receptor containing the cytoplasmic domain being predominant in human exosomes.

Acetylcholinesterase↗

PubMed2006

Microarray detection of novel nuclear RNA substrates for the exosome.

Microarray analyses were performed on yeast strains mutant for the nuclear-specific exosome components Rrp6p and Rrp47p/Lrp1p or the core component Rrp41p/Ski6p, at permissive temperature and following transfer to 37 degrees C. 339 mRNAs showed clearly altered expression levels, with an unexpectedly high degree of heterogeneity in the different exosome mutants. In contrast, no clear alterations were seen in strains lacking the cytoplasmic exosome component Ski7p. 27 mRNAs that were overexpressed in each strain defective in the nuclear exosome are good candidates for regulation by nuclear turnover. These included the mRNA for the autoregulated RNA-binding protein Nrd1p. Northern and primer extension analyses confirmed the elevated NRD1 mRNA levels in exosome mutants, and revealed the accumulation of truncated 5' fragments of the mRNA. These contain a predicted Nrd1p-binding site, potentially sequestering the protein and disrupting its autoregulation. Several genes located immediately downstream of independently transcribed snoRNA genes were overexpressed in exosome mutants, presumably due to stabilization of the products of transcription termination read-through. Further analyses indicated that many snoRNA and snRNA genes are inefficiently terminated, but read-through transcripts into downstream ORFs are normally rapidly degraded by the exosome.

Blotting, Northern↗

PubMed2003

Exosomes for immunotherapy of cancer.

Exosomes are 60 to 90 nm membrane vesicles originating from late endosomes and secreted from most hematopoietic and epithelial cells in vitro. B cell derived-exosome antigenicity was first reported in 1996 in MHC class II restricted CD4+ T lymphocytes. In 1998, we reported that dendritic cell derived-exosomes are immunogenic in mice leading to tumor rejection. These findings have renewed the interest in exosomes. The current challenge consists in understanding the mechanisms and the physiological relevance of exosomes that could contribute to the design of the optimal exosome based-vaccination. Here, we will focus on the biological features pertaining to dendritic cell- and tumor cell derived-exosomes and will discuss their potential clinical implementation.

Animals↗

PubMed2006

Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells.

Dendritic cells (DC)-derived or tumor-derived exosomes are a population of nanometer sized membrane vesicles that can induce specific anti-tumor immunity. However, the immunogenic potential and efficiency of exosomes-based tumor vaccine are not satisfactory enough to achieve a curative effect in clinical trials. In this article we investigated whether IL-18 genetic modification of tumor cells can increase the efficacy of exosomes derived from IL-18 gene-modified tumor cells. We transfected carcinoembryonic antigen (CEA)-expressing tumor cells with a recombinant adenovirus encoding human IL-18 (AdhIL-18) and prepared the exosomes, Exo/IL-18, from IL-18 gene-modified tumor cells. We found that Exo/IL-18 naturally contain CEA and bioactive IL-18. Moreover, Exo-IL-18 are potent in chemoattracting DC and T cells, enhancing the proliferation and Th1 cytokine release of PBMC, and promoting the phenotypic and functional maturation of DC. Furthermore, Exo/IL-18-pulsed DC are quite potent to induce HLA-A*0201-restricted, CEA-specific CD8(+) CTL from the PBMC of HLA-A*0201 CEA(+) cancer patients in vitro. In almost all of these experiments, Exo/IL-18 show more potent functions than the conventionally prepared exosomes derived from parent tumor cells without IL-18 gene modification. Our findings suggest that Exo/IL-18 has more potent capability to induce specific anti-tumor immunity, and our strategy of IL-18 modification of exosomes is a feasible approach to develop exosomes-based tumor vaccines.

Adenoviridae↗

PubMedDate not supplied

Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis.

Tumor-derived immune suppression is considered to be a major mechanism of tumor evasion from the immune system destruction, however, little is known regarding the induction of T-cell functional suppression by tumor-derived exosomes. Herein, we investigate tumor-derived exosomes involved in normal immunological communications as means of inhibiting an antitumor T-cell response. Exosomes derived from LNCaP, a human prostate cancer cell line, were visualized by FACS and identified based on size (80-200 nm) in comparison to marker beads. Exosomes from tumor cell line inhibited T-cell proliferation. Dose-dependent apoptosis of T cells was induced by co-culture with tumor exosomes. Addition of anti-FasL antibody blocked the apoptosis induction by tumor exosomes. This study suggests that induction of T-cell apoptosis by tumor-derived exosomes appears to be a novel mechanism of tumor immune evasion.

Antigens, Neoplasm↗

PubMed2006

A new role of diacylglycerol kinase alpha on the secretion of lethal exosomes bearing Fas ligand during activation-induced cell death of T lymphocytes.

Exosomes are small membrane vesicles that intracellularly accumulate into late or multivesicular endosomes (multivesicular bodies, MVB). Exosomes have a particular lipid and protein content, reflecting their origin as intraluminal vesicles of late endosomes. The stimulation of several hematopoietic cells induces the fusion of the limiting membrane of the MVB with the plasma membrane, leading to the release of exosomes towards the extracellular environment. In T lymphocytes, stimulation of the T cell receptor (TCR) induces the fusion of the MVBs with the plasma membrane and exosomes carrying several bio-active proteins are secreted. Among these proteins, the pro-apoptotic protein Fas ligand (FasL) is released as a non-proteolysed form (mFasL), associated to the exosomes. These mFasL-bearing exosomes may trigger the apoptosis of T lymphocytes. Here, we present evidences supporting a role of diacylglycerol kinase alpha (DGKalpha), a diacylglycerol (DAG)-consuming enzyme, on the secretion of exosomes carrying mFasL, and the subsequent activation-induced cell death (AICD) on a T cell line and primary T lymphoblasts.

Apoptosis↗

PubMed2005

Exosomes secreted from monocyte-derived dendritic cells support in vitro naive CD4+ T cell survival through NF-(kappa)B activation.

We investigated the effect of exosomes secreted from human monocyte-derived dendritic cells (Mo-DCs), which are generated from PBMCs in response to treatment with GM-CSF and IL-4, on naive CD4+ T cell survival in vitro. Exosomes isolated from culture supernatants of Mo-DCs (>90% purity) were purified with anti-HLA-DP, -DQ, -DR-coated paramagnetic beads. Purified exosomes prolonged the survival of naive CD4+ T cells (>98% purity) in vitro. Treatment with neutralizing mAb against HLA-DR significantly decreased the supportive effect of purified exosomes on CD4+ T cell survival. Exosomes increased nuclear translocation of NF-(kappa)B in naive CD4+ T cells, and NF-(kappa)B activation was significantly suppressed by anti-HLA-DR mAb or NF-(kappa)B inhibitor pyrrolidine dithiocarbamate (PDTC). In addition, PDTC inhibited the effect of exosomes on naive CD4+ T cell survival. Thus, exosomes secreted by Mo-DCs appear to support naive CD4+ T cell survival via NF-(kappa)B activation induced by interaction of HLA-DR and TCRs.

Antigens, CD↗

PubMed2006

Exosomes: from biogenesis and secretion to biological function.

Exosomes are small microvesicles that are released from late endosomal compartments of cultured cells. Recent work has shown that exosome-like vesicles are also found in many body fluids such as blood, urine, ascites and amnionic fluid. Although the biological function of exosomes is far from being fully understood, exosomes may have general importance in cell biology and immunology. The present review aims to address some of the facets of exosome research with particular emphasis on the immunologist's perspective: (i) exosomes as a novel platform for the ectodomain shedding of membrane proteins by ADAMs and (ii) recent findings on the role of exosomes in tumor biology and immune regulation.

Animals↗

PubMed2006

Exosomes are released by cultured cortical neurones.

Accumulating evidence shows that several cell types have the capacity to secrete membrane proteins by incorporating them into exosomes, which are small lipid vesicles derived from the intralumenal membranes of multivesicular bodies (MVBs) of the endocytic pathway. Exosomes are expelled in the extracellular space upon fusion of the MVB with the plasma membrane. Exosomal release is a way of secreting membrane proteins meant to be discarded, or to be passed on to other cells. Here, we demonstrate, using primary cortical cultures, that neurones and astrocytes can secrete exosomes. We find that exosomes released by cortical neurones contain the L1 cell adhesion molecule, the GPI-anchored prion protein, and the GluR2/3 but not the NR1 subunits of glutamate receptors. We also show that exosomal release is regulated by depolarisation. Our observation suggests that exosomes may have a regulatory function at synapses and could also allow intercellular exchange of membrane proteins within the brain.

Animals↗

PubMed2003

MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells.

Exosomes are 50-90 nm vesicles with antigen presenting ability carrying major histocompatibility complex (MHC) class I, class II, abundant co-stimulatory molecules and some tetraspan proteins. Although dendritic cells (DCs) are one of the professional antigen presenting cells capable of presenting exogenous antigens in MHC class I-mediated antigen specific manner (cross-presentation), the cross-presentation ability by exosomes from immature or mature DCs are unknown. Here we show that exosomes released from ovalbumin (OVA) protein-pulsed bone marrow derived dendritic cells (BM-DCs) weakly present the peptide determinants to OVA specific MHC class I-restricted CD8(+) T cell hybridomas. The exosomes secreted by OVA(257-264) peptide- or OVA protein-pulsed mature BM-DCs activated OVA specific MHC class I-restricted T cell hybridomas more efficiently than those from immature BM-DCs. Transporters associated with antigen processing (TAP) deficient mice-derived BM-DCs were also used to examine whether functional TAP activity was required for cross-presentation by exosomes. The exosomes obtained from OVA(257-264) peptide-pulsed BM-DCs derived from TAP(-/-) mice showed a significant antigen presenting ability to OVA specific MHC class I-restricted T cell hybridomas. Altogether, our data indicate that BM-DCs secrete exosomes with weak cross-presentation ability.

Animals↗