Nutrient availability regulates the secretion and function of immune cell–derived extracellular vesicles through metabolic rewiring
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC10866539 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:Extracellular Vesicles (EVs) are a heterogenous population of particles that play an important role in cell-cell communication in physiological and pathophysiological situations. In this study we reveal that the peptidyl prolyl isomerase Cyclophilin A (CypA) is enriched in cancer-derived EVs from a range of haematopoietic malignancies. CypA-enriched blood cancer EVs were taken up by normal monocytes independent of EV surface trypsin-sensitive proteins and potently stimulated pro-inflammatory MMP9 and IL-6 secretion. Further characterisation revealed that CypA is intravesicular, however, it is not present in all EVs derived from the haematopoietic cells, instead, it is predominantly located in high density EVs with a range of 1.15-1.18 g/ml. Furthermore, loss of CypA expression in haematological cancer cells attenuates high density EV-induced pro-inflammatory MMP9 and IL-6 secretion from monocytes. Mechanistically, we reveal that homozygous loss or siRNA knockdown of CypA expression significantly reduced the secretion of EVs in the range of 100-200 nm from blood cancer cells under normal and hypoxic conditions. Overall, this work reveals a novel role for CypA in cancer cell EV biogenesis.
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Project description:BackgroundPrevious research has revealed that KIBRA controls secretion of extracellular vesicles (EVs) by inhibiting the proteasomal degradation of Rab27a and EVs play an important role in amyloid β (Aβ) metabolism and transmission during Alzheimer's disease (AD) pathogenesis. Here, we further test the hypothesis that KIBRA regulates Aβ metabolism via the endosomal-lysosomal system.MethodsWe generated KIBRA knockout mice on a 5XFAD background and KIBRA knockdown cells in murine HT22 cells with stably overexpressing APP. Various forms of Aβ and quantification of EVs were analyzed by biochemical methods and nanoparticle tracking analysis, respectively. Multivesicular bodies (MVBs) were visualized by electron microscopy and confocal fluorescent microscopy. In a population-based cohort (n = 1419), KIBRA genotypes and plasma Aβ levels were analyzed using multiple-PCR amplification and Simoa, respectively.FindingsMultiple forms of Aβ were dramatically attenuated in KIBRA knockout mouse brain, including monomers, oligomers, and extracellular deposition, but KIBRA knockout had no effect on intraneuronal APP C-terminal fragment β (APP-CTFβ)/Aβ levels. KIBRA depletion also decreased APP-CTFβ/Aβ-associated EVs secretion and subsequently enhanced MVBs number. Furthermore, we found that excessive accumulation of MVBs harboring APP-CTFβ/Aβ promoted the MVBs-lysosome fusion for degradation and inhibition of lysosomal function rescued secretion of APP-CTFβ/Aβ-associated EVs. More importantly, whole exon sequencing of KIBRA in a large population-based cohort identified the association of KIBRA rs28421695 polymorphism with plasma Aβ levels.InterpretationThese results demonstrate that KIBRA regulates Aβ metabolism via controlling the secretion of APP-CTFβ/Aβ-associated EVs.FundingNational Key R&D Program of China, and National Natural Science Foundation of China.
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Project description:BackgroundGlioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation.MethodsHealthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity.ResultsProtein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells.ConclusionThe differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.
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Project description:Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NK-cell-derived extracellular vesicles (NKEVs) are constitutively secreted and biologically active. They reflect the protein and genetic repertoire of originating cells, and exert antitumor activity in vitro and in vivo. Cancer can compromise NK cell functions, a status potentially reflected by their extracellular vesicles. Hence, NKEVs could, on the one hand, contribute to improve cancer therapy by interacting with tumor and/or immune cells and on the other hand, sense the actual NK cell status in cancer patients. Here, we investigated the composition of healthy donors' NKEVs, including NK microvesicles and exosomes, and their interaction with uncompromised cells of the immune system. To sense the systemic NK cell status in cancer patients, we developed an immune enzymatic test (NKExoELISA) that measures plasma NK-cell-derived exosomes, captured as tsg101+CD56+ nanovesicles. NKEV mass spectrometry and cytokine analysis showed the expression of NK cell markers, i.e., NKG2D and CD94, perforin, granzymes, CD40L, and other molecules involved in cytotoxicity, homing, cell adhesion, and immune activation, together with EV markers tsg101, CD81, CD63, and CD9 in both NK-derived exosomes and microvesicles. Data are available via Proteome Xchange with identifier PXD014894. Immunomodulation studies revealed that NKEVs displayed main stimulatory functions in peripheral blood mononuclear cells (PBMCs), inducing the expression of human leukocyte antigen DR isotype (HLA-DR) and costimulatory molecules on monocytes and CD25 expression on T cells, which was maintained in the presence of lipopolysaccharide (LPS) and interleukin (IL)-10/transforming growth factor beta (TGFβ), respectively. Furthermore, NKEVs increased the CD56+ NK cell fraction, suggesting that effects mediated by NKEVs might be potentially exploited in support of cancer therapy. The measurement of circulating NK exosomes in the plasma of melanoma patients and healthy donors evidenced lower levels of tsg101+CD56+ exosomes in patients with respect to donors. Likewise, we detected lower frequencies of NK cells in PBMCs of these patients. These data highlight the potential of NKExoELISA to sense alterations of the NK cell immune status.
| S-EPMC7082405 | biostudies-literature
Project description:Tumor-derived extracellular vesicles (TDEVs) play crucial roles in intercellular communication both in the local tumor microenvironment and systemically, facilitating tumor progression and metastatic spread. They carry a variety of molecules with bioactive properties, such as nucleic acids, proteins and metabolites, that trigger different signaling processes in receptor cells and induce, among other downstream effects, metabolic reprogramming. Interestingly, the cargo of TDEVs also reflects the metabolic status of the producing cells in a time- and context-dependent manner, providing information on the functionality and state of those cells. For these reasons, together with their ability to be detected in diverse biofluids, there is increasing interest in the study of TDEVs, particularly their metabolic cargo, as diagnostic and prognostic tools in cancer management. This review presents a compilation of metabolism-related molecules (enzymes and metabolites) described in cancer extracellular vesicles (EVs) with potential use as cancer biomarkers, and discusses the challenges arising in this rapidly evolving field.
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Project description:The placenta releases large quantities of extracellular vesicles (EVs) that likely facilitate communication between the embryo/fetus and the mother. We isolated EVs from second trimester human cytotrophoblasts (CTBs) by differential ultracentrifugation and characterized them using transmission electron microscopy, immunoblotting and mass spectrometry. The 100,000 g pellet was enriched for vesicles with a cup-like morphology typical of exosomes. They expressed markers specific to this vesicle type, CD9 and HRS, and the trophoblast proteins placental alkaline phosphatase and HLA-G. Global profiling by mass spectrometry showed that placental EVs were enriched for proteins that function in transport and viral processes. A cytokine array revealed that the CTB 100,000 g pellet contained a significant amount of tumor necrosis factor α (TNFα). CTB EVs increased decidual stromal cell (dESF) transcription and secretion of NF-κB targets, including IL8, as measured by qRT-PCR and cytokine array. A soluble form of the TNFα receptor inhibited the ability of CTB 100,000 g EVs to increase dESF secretion of IL8. Overall, the data suggest that CTB EVs enhance decidual cell release of inflammatory cytokines, which we theorize is an important component of successful pregnancy.
| S-EPMC7502596 | biostudies-literature
Project description:BackgroundSeveral studies demonstrate the role of adipose mesenchymal stem cells (ASCs) in angiogenesis. The angiogenic mechanism has been ascribed to paracrine factors since these cells secrete a plenty of signal molecules and growth factors. Recently it has been suggested that besides soluble factors, extracellular vesicles (EVs) that include exosomes and microvesicles may play a major role in cell-to-cell communication. It has been shown that EVs are implicated in the angiogenic process.ResultsHerein we studied whether EVs released by ASCs may mediate the angiogenic activity of these cells. Our results demonstrated that ASC-derived EVs induced in vitro vessel-like structure formation by human microvascular endothelial cells (HMEC). EV-stimulated HMEC when injected subcutaneously within Matrigel in SCID mice formed vessels. Treatment of ASCs with platelet-derived growth factor (PDGF) stimulated the secretion of EVs, changed their protein composition and enhanced the angiogenic potential. At variance of EVs released in basal conditions, PDGF-EVs carried c-kit and SCF that played a role in angiogenesis as specific blocking antibodies inhibited in vitro vessel-like structure formation. The enhanced content of matrix metalloproteinases in PDGF-EVs may also account for their angiogenic activity.ConclusionsOur findings indicate that EVs released by ASCs may contribute to the ASC-induced angiogenesis and suggest that PDGF may trigger the release of EVs with an enhanced angiogenic potential.
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Project description:Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.
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Project description:The arterial mechanical microenvironment, including stiffness, is a crucial pathophysiological feature of vascular remodeling, such as neointimal hyperplasia after carotid endarterectomy and balloon dilatation surgeries. In this study, we examined changes in neointimal stiffness in a Sprague-Dawley rat carotid artery intimal injury model and revealed that extracellular matrix (ECM) secretion and vascular stiffness were increased. Once the endothelial layer is damaged in vivo, activated platelets adhere to the intima and may secrete platelet-derived extracellular vesicles (pEVs) and communicate with vascular smooth muscle cells (VSMCs). In vitro, pEVs stimulated VSMCs to promote collagen secretion and cell adhesion. MRNA sequencing analysis of a carotid artery intimal injury model showed that ECM factors, including col8a1, col8a2, col12a1, and elastin, were upregulated. Subsequently, ingenuity pathway analysis (IPA) was used to examine the possible signaling pathways involved in the formation of ECM, of which the Akt pathway played a central role. In vitro, pEVs activated Akt signaling through the PIP3 pathway and induced the production of Col8a1. MicroRNA (miR) sequencing of pEVs released from activated platelets revealed that 14 of the top 30 miRs in pEVs targeted PTEN, which could promote the activation of the Akt pathway. Further research showed that the most abundant miR targeting PTEN was miR-92a-3p, which promoted Col8a1 expression. Interestingly, knockdown of Col8a1 expression in vivo abrogated the increase in carotid artery stiffness and simultaneously increased the degree of neointimal hyperplasia. Our results revealed that pEVs may deliver miR-92a-3p to VSMCs to induce the production and secretion of Col8a1 via the PTEN/PIP3/Akt pathway, subsequently increasing vascular stiffness. Therefore, pEVs and key molecules may be potential therapeutic targets for treating neointimal hyperplasia.
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Project description:Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.
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