Journal of Extracellular Vesicles最新文献

{"title":"Breast Cancer-Derived Extracellular Vesicles Modulate the Cytoplasmic and Cytoskeletal Dynamics of Blood-Brain Barrier Endothelial Cells","authors":"Sara Busatto,&nbsp;Tzu-Hsi Song,&nbsp;Hyung Joon Kim,&nbsp;Caleb Hallinan,&nbsp;Michael N. Lombardo,&nbsp;Anat O. Stemmer-Rachamimov,&nbsp;Kwonmoo Lee,&nbsp;Marsha A. Moses","doi":"10.1002/jev2.70038","DOIUrl":"10.1002/jev2.70038","url":null,"abstract":"<p>Extracellular vesicles (EVs) from brain-seeking breast cancer cells (Br-EVs) breach the blood-brain barrier (BBB) via transcytosis and promote brain metastasis. Here, we defined the mechanisms by which Br-EVs modulate brain endothelial cell (BEC) dynamics to facilitate their BBB transcytosis. BEC treated with Br-EVs show significant downregulation of Rab11fip2, known to promote vesicle recycling to the plasma membrane and significant upregulation of Rab11fip3 and Rab11fip5, which support structural stability of the endosomal compartment and facilitate vesicle recycling and transcytosis, respectively. Using machine learning and quantitative global proteomic, we identified novel Br-EV-induced changes in BECs morphology, motility, and proteome that correlate with decreased BEC cytoplasm and cytoskeletal organization and dynamics. These results define early steps leading to breast-to-brain metastasis and identify molecules that could serve as targets for therapeutic strategies for brain metastasis.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intercellular Epigenomic Signalling via Extracellular Vesicles During B Cell Maturation","authors":"Kevin Ho Wai Yim,&nbsp;Ala'a Al Hrout,&nbsp;Richard Chahwan","doi":"10.1002/jev2.70040","DOIUrl":"10.1002/jev2.70040","url":null,"abstract":"<p>B cell maturation is crucial for effective adaptive immunity. It requires a complex signalling network to mediate antibody diversification through mutagenesis. B cells also rely on queues from other cells within the germinal centre. Recently, a novel class of intercellular signals mediated by extracellular vesicles (EVs) has emerged. Studies have shown that B cell EV-mediated signalling is involved in immune response regulation and tumorigenesis. However, the mechanistic role of B cell EVs is not yet established. We herein study the biological properties and physiological function of B cell EVs during B cell maturation. We use emerging technologies to profile B cell EV surface marker signatures at the single particle level, molecular cargo and physiological roles in B cell maturation. EV ncRNA cargo, characterised by RNA-seq, identified an EV-mediated novel non-coding RNA (ncRNA) regulatory network for B cell maturation. We show that a previously uncharacterised micro-RNA (miR-5099) in combination with a set of long ncRNA are carried within B cell EVs and could contribute to antibody diversification. The physiological role of EVs in B cell maturation is investigated using EV blockade assays and complementation studies using diverse EV sources further confirmed the physiological role and mode of action of EVs in B cell maturation.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles From Bone Marrow-Derived Macrophages Enriched in ARG1 Enhance Microglial Phagocytosis and Haematoma Clearance Following Intracerebral Haemorrhage","authors":"Libin Hu,&nbsp;Zihang Chen,&nbsp;Jianglong Lu,&nbsp;Shandong Jiang,&nbsp;Haopu Lin,&nbsp;Jiayin Zhou,&nbsp;Ning Wang,&nbsp;Chao Ding,&nbsp;Weifang Ni,&nbsp;Haitao Peng,&nbsp;Yin Li,&nbsp;Xuchao He,&nbsp;Jianru Li,&nbsp;Chaohui Jing,&nbsp;Yang Cao,&nbsp;Hang Zhou,&nbsp;Feng Yan,&nbsp;Gao Chen","doi":"10.1002/jev2.70041","DOIUrl":"10.1002/jev2.70041","url":null,"abstract":"<p>Microglial phagocytosis of haematomas is crucial for neural functional recovery following intracerebral haemorrhage (ICH), a process regulated by various factors from within and outside the central nervous system (CNS). Extracellular vesicles (EVs), significant mediators of intercellular communication, have been demonstrated to play a pivotal role in the pathogenesis and progression of CNS diseases. However, the regulatory role of endogenous EVs on the phagocytic capacity of microglia post-ICH remains elusive. Utilising multi-omics analysis of brain tissue-derived EVs proteomics and single-cell RNA sequencing, this study identified that bone marrow-derived macrophages (BMDMs) potentially enhance microglial phagocytosis via EVs following ICH. By blocking BMDMs and reducing ARG1 in BMDM-derived EVs, we demonstrated that BMDMs facilitate erythrophagocytosis by delivering ARG1 to microglia via EVs post-ICH. EVs-carried ARG1 was found to augment phagocytosis by promoting RAC1-dependent cytoskeletal remodelling in microglia. Collectively, this research uncovers an intercellular communication pathway from BMDMs to microglia mediated by EVs post-ICH. This provides a novel paradigm for EV-mediated intercellular communication mechanisms and suggests a promising therapeutic potential for BMDM-derived EVs in the treatment of ICH.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering a new family of conserved virulence factors that promote the production of host-damaging outer membrane vesicles in gram-negative bacteria","authors":"Audrey Goman,&nbsp;Bérengère Ize,&nbsp;Katy Jeannot,&nbsp;Camille Pin,&nbsp;Delphine Payros,&nbsp;Cécile Goursat,&nbsp;Léa Ravon-Katossky,&nbsp;Kazunori Murase,&nbsp;Camille V. Chagneau,&nbsp;Hélène Revillet,&nbsp;Frédéric Taieb,&nbsp;Sophie Bleves,&nbsp;Laure David,&nbsp;Etienne Meunier,&nbsp;Priscilla Branchu,&nbsp;Eric Oswald","doi":"10.1002/jev2.70032","DOIUrl":"10.1002/jev2.70032","url":null,"abstract":"<p>CprA is a short-chain dehydrogenase/reductase (SDR) that contributes to resistance against colistin and antimicrobial peptides. The <i>cprA</i> gene is conserved across <i>Pseudomonas aeruginosa</i> clades and its expression is directly regulated by the two-component system PmrAB. We have shown that <i>cprA</i> expression leads to the production of outer membrane vesicles (OMVs) that block autophagic flux and have a greater capacity to activate the non-canonical inflammasome pathway. In a murine model of sepsis, a <i>P. aeruginosa</i> strain deleted for <i>cprA</i> was less virulent than the wild-type (WT) strain. These results demonstrate the important role of CprA in the pathogenicity of <i>P. aeruginosa</i>. It is worth noting that CprA is also a functional ortholog of hemolysin F (HlyF), which is encoded by virulence plasmids of <i>Escherichia coli</i>. We have shown that other cryptic SDRs encoded by mammalian and plant pathogens, such as <i>Yersinia pestis</i> and <i>Ralstonia solanacearum</i> are functional orthologs of CprA and HlyF. These SDRs also induce the production of OMVs which block autophagic flux. This study uncovers a new family of virulence determinants in Gram-negative bacteria, offering potential for innovative therapeutic interventions and deeper insights into bacterial pathogenesis.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Non-Centrifugation Method to Concentrate and Purify Extracellular Vesicles Using Superabsorbent Polymer Followed by Size Exclusion Chromatography","authors":"Markus Bergqvist,&nbsp;Cecilia Lässer,&nbsp;Rossella Crescitelli,&nbsp;Kyong-Su Park,&nbsp;Jan Lötvall","doi":"10.1002/jev2.70037","DOIUrl":"10.1002/jev2.70037","url":null,"abstract":"<p>Extracellular vesicles (EVs) can be isolated and purified from cell cultures and biofluids using different methodologies. Here, we explored a novel EV isolation approach by combining superabsorbent polymers (SAP) in a dialysis membrane with size exclusion chromatography (SEC) to achieve high concentration and purity of EVs without the use of ultracentrifugation (UC). Suspension HEK293 cells transfected with CD63 coupled with Thermo Luciferase were used to quantify the EV yield and purity. The 500 mL conditioned medium volume was initially reduced by pressure ultrafiltration, followed by UC, SAP or a centrifugal filter unit (CFU). Using either of these methods, the EVs were concentrated to a final volume of approximately 1 mL, with retained functionality. The yield, quantified by luciferase activity, was highest with UC (70%–80%), followed by SAP (60%–70%) and CFU (50%–60%). Further purification of the EVs was performed by iodixanol density cushion (IDC) or SEC (Sepharose CL-2B or 6B, in either 10 or 20 mL columns). Although the IDC and Sepharose CL-2B (10 mL) achieved the highest yields, the purity was slightly higher (30%) with IDC. In conclusion, combining SAP concentration with CL-2B SEC is an alternative and efficient way to isolate EVs without using UC.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Phenotyping of Extracellular Vesicles in Plasma of Healthy Humans – Insights Into Cellular Origin and Biological Variation","authors":"Marija Holcar,&nbsp;Ivica Marić,&nbsp;Tobias Tertel,&nbsp;Katja Goričar,&nbsp;Urška Čegovnik Primožič,&nbsp;Darko Černe,&nbsp;Bernd Giebel,&nbsp;Metka Lenassi","doi":"10.1002/jev2.70039","DOIUrl":"10.1002/jev2.70039","url":null,"abstract":"<p>Despite immense interest in biomarker applications of extracellular vesicles (EVs) from blood, our understanding of circulating EVs under physiological conditions in healthy humans remains limited. Using imaging and multiplex bead-based flow cytometry, we comprehensively quantified circulating EVs with respect to their cellular origin in a large cohort of healthy blood donors. We assessed coefficients of variations to characterize their biological variation and explored demographic, clinical, and lifestyle factors contributing to observed variation. Cell-specific circulating EV subsets show a wide range of concentrations that do not correlate with cell-of-origin concentrations in blood, suggesting steady-state EV subset concentrations are regulated by complex mechanisms, which differ even for EV subsets from the same cell type. Interestingly, tetraspanin+ circulating EVs largely originate from platelets and to a lesser extent from lymphocytes. Principal component analysis (PCA) and association analyses demonstrate high biological inter-individual variation in circulating EVs across healthy humans, which are only partly explained by the influence of sex, menopausal status, age and smoking on specific circulating EV and/or tetraspanin+ circulating EV subsets. No global influence of the explored subject's factors on circulating EVs was detected. Our findings provide the first comprehensive, quantitative data towards the cell-origin atlas of plasma EVs, with important implications in the clinical use of EVs as biomarkers.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reproducibility of extracellular vesicle research","authors":"Rossella Crescitelli,&nbsp;Juan Falcon-Perez,&nbsp;An Hendrix,&nbsp;Metka Lenassi,&nbsp;Le Thi Nguyet Minh,&nbsp;Takahiro Ochiya,&nbsp;Nicole Noren Hooten,&nbsp;Ursula Sandau,&nbsp;Clotilde Théry,&nbsp;Rienk Nieuwland","doi":"10.1002/jev2.70036","DOIUrl":"10.1002/jev2.70036","url":null,"abstract":"&lt;p&gt;Ever since its launch in 2011, the International Society for Extracellular Vesicles (ISEV) has endorsed, initiated, and supported original ideas and solutions to promote reproducibility (Hill et al., &lt;span&gt;2013&lt;/span&gt;; Lötvall et al., &lt;span&gt;2014&lt;/span&gt;; Théry et al., &lt;span&gt;2018&lt;/span&gt;; Welsh et al., &lt;span&gt;2024&lt;/span&gt;) and these efforts have been appreciated by the general scientific community (Abbott, &lt;span&gt;2023&lt;/span&gt;). Improving reproducibility is complex and multifactorial, and involves development of protocols, reference materials and standards, interlaboratory comparison studies, instrument calibration, transparent reporting, and education.&lt;/p&gt;&lt;p&gt;To support reproducibility, ISEV founded the Rigor and Standardization (R&amp;S) Subcommittee in 2019, which now includes fifteen task forces and three inter-societal working groups (https://www.isev.org/rigor-standardization). Within this subcommittee, hundreds of ISEV members have become actively involved in R&amp;S, and together they are working on creative solutions to overcome the challenges of reproducibility in the EV field.&lt;/p&gt;&lt;p&gt;EV research invariably involves collection, handling, and storage of (EV-containing) fluids, such as body fluids and conditioned culture media, and tissues, which are the starting materials for EV research. Collection, handling and storage of (purified) EV-containing materials will affect their composition. For example, preparation of plasma and serum, which are amongst the most commonly used body fluids for EV research (Royo et al., &lt;span&gt;2020&lt;/span&gt;), involves about 40 variables which all may impact the sample composition and downstream analysis of EVs (Clayton et al., &lt;span&gt;2019&lt;/span&gt;). Laboratories and biobanks preparing and storing EV-containing tissues and fluids, commonly use their own ‘in-house’ protocols, which all may differ from each other and have unknown effects on the sample composition and downstream analysis of EVs (López-Guerrero et al., &lt;span&gt;2023&lt;/span&gt;). Moreover, even when the same protocol is used, the sample composition may still vary (Bettin et al., &lt;span&gt;2022&lt;/span&gt;) and these differences can be sufficient to affect the results of downstream EV characterization (Bracht et al., &lt;span&gt;2023&lt;/span&gt;). Taken together, sample preparation and storage invariably leads to variability in sample composition, thereby introducing an ‘uneven playing field’ and bias which can hamper the comparability, interpretation and reproducibility of results on EVs.&lt;/p&gt;&lt;p&gt;At present, the current approach to improve reproducibility is by reporting the protocol of sample preparation in the Materials and Methods section of scientific manuscripts. Unfortunately, this reporting is often incomplete or inconsistent between manuscripts, thereby hampering reproducibility. There can be multiple reasons for incomplete or inconsistent reporting, ranging from researchers not knowing these details themselves, or because the journal has a strict word count, or the details are con","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular RNA communication: A decade of NIH common fund support illuminates exRNA biology","authors":"Sara M. Amolegbe,&nbsp;Nicolas C. Johnston,&nbsp;Angela Ambrosi,&nbsp;Aniruddha Ganguly,&nbsp;T. Kevin Howcroft,&nbsp;Lillian S. Kuo,&nbsp;Patricia A. Labosky,&nbsp;Dobrila D. Rudnicki,&nbsp;John S. Satterlee,&nbsp;Danilo A. Tagle,&nbsp;Christine Happel","doi":"10.1002/jev2.70016","DOIUrl":"10.1002/jev2.70016","url":null,"abstract":"<p>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.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helminth extracellular vesicles co-opt host monocytes to drive T cell anergy","authors":"Anne Borup,&nbsp;Mohammad Farouq Sharifpour,&nbsp;Litten S. Rossen,&nbsp;Bradley Whitehead,&nbsp;Anders T. Boysen,&nbsp;Rikke Olesen,&nbsp;Anja B. Bohn,&nbsp;Andrea Ridolfi,&nbsp;Marco Brucale,&nbsp;Francesco Valle,&nbsp;Lucia Paolini,&nbsp;Annalisa Radeghieri,&nbsp;Paolo Bergese,&nbsp;Kim Miles,&nbsp;Margaret Veitch,&nbsp;Tamara Thomas,&nbsp;Roland Ruscher,&nbsp;Phurpa Wangchuk,&nbsp;Paul Giacomin,&nbsp;Alex Loukas,&nbsp;Peter Nejsum","doi":"10.1002/jev2.70027","DOIUrl":"10.1002/jev2.70027","url":null,"abstract":"<p>Parasitic helminths secrete extracellular vesicles (EVs) into their host tissues to modulate immune responses, but the underlying mechanisms are poorly understood. We demonstrate that <i>Ascaris</i> EVs are efficiently internalised by monocytes in human peripheral blood mononuclear cells and increase the percentage of classical monocytes. Furthermore, EV treatment of monocytes induced a novel anti-inflammatory phenotype characterised by CD14⁺, CD16⁻, CC chemokine receptor 2 (CCR2⁻) and programmed death-ligand 1 (PD-L1)⁺ cells. In addition, <i>Ascaris</i> EVs induced T cell anergy in a monocyte-dependent mechanism. Targeting professional phagocytes to induce both direct and indirect pathways of immune modulation presents a highly novel and efficient mechanism of EV-mediated host-parasite communication. Intra-peritoneal administration of EVs induced protection against gut inflammation in the dextran sodium sulphate model of colitis in mice. <i>Ascaris</i> EVs were shown to affect circulating immune cells and protect against gut inflammation; this highlights their potential as a subject for further investigation in inflammatory conditions driven by dysregulated immune responses. However, their clinical translation would require further studies and careful consideration of ethical implications.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presenilins as hub proteins controlling the endocytic and autophagic pathways and small extracellular vesicle secretion","authors":"Inger Lauritzen,&nbsp;Anaïs Bini,&nbsp;Anaïs Bécot,&nbsp;Anne-Sophie Gay,&nbsp;Céline Badot,&nbsp;Sophie Pagnotta,&nbsp;Mounia Chami,&nbsp;Frédéric Checler","doi":"10.1002/jev2.70019","DOIUrl":"10.1002/jev2.70019","url":null,"abstract":"<p>Emerging evidence indicates that autophagy is tightly connected to the endocytic pathway. Here, we questioned the role of presenilins (PSENs 1 and 2), previously shown to be involved in autophagy regulation, in the secretion of small endocytic-originating extracellular vesicles known as exosomes. Indeed, while wild-type cells responded to stimuli promoting both multivesicular endosome (MVE) formation and secretion of small extracellular vesicles (sEVs) enriched in canonical exosomal proteins, PSEN-deficient cells were almost unaffected to these stimuli. Moreover, in PSEN-deficient cells, the re-expression of either PSEN1 or the functional active PSEN1delta9 mutant led to a rescue of most sEV secretion, while the deletion of PSEN1 alone almost fully phenocopied total PSEN invalidation. We found that the lack of sEV secretion in PSEN-deficient cells was also due to overactivated autophagy promoting MVEs to degradation rather than to plasma membrane fusion. Hence, in these cells, the autophagic blocker bafilomycin A1 (BafA1) not only increased the intracellular levels of the MVE protein CD63, but also turned on sEV secretion by stimulating autophagy-dependent unconventional secretion. In that case, sEVs arised from amphisomes and were enriched in both canonical exosomal proteins and lysosomal-autophagy-associated cargo. Altogether, we here demonstrate that PSENs, and particularly PSEN1, act as hub proteins controlling the balance between endosomal/autophagic degradation and secretion. More generally, our findings strengthen the view of a strong interconnection between the endocytic and autophagic pathways and their complementary roles in sEV secretion.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 1","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}