Journal of Extracellular Vesicles最新文献

{"title":"Extracellular Vesicles From Xylella fastidiosa Carry sRNAs and Genomic Islands, Suggesting Roles in Recipient Cells","authors":"Alessa Ruf,&nbsp;Patrick Blumenkamp,&nbsp;Christina Ludwig,&nbsp;Anne Lippegaus,&nbsp;Andreas Brachmann,&nbsp;Andreas Klingl,&nbsp;Alexander Goesmann,&nbsp;Karina Brinkrolf,&nbsp;Kai Papenfort,&nbsp;Silke Robatzek","doi":"10.1002/jev2.70102","DOIUrl":"https://doi.org/10.1002/jev2.70102","url":null,"abstract":"<p><i>Xylella fastidiosa</i> (<i>Xf</i>) is a Gram-negative bacterial plant pathogen responsible for severe diseases in a variety of economically important crops. A critical aspect of its virulence is the production of extracellular vesicles (EVs). In this study, we discovered that DNA-binding proteins and nonribosomal RNA-binding proteins are abundant in the corona of <i>Xf</i>-EVs. DNA-seq revealed enrichment of three genomic islands (GIs) in EVs, which carry molecular signatures indicative of horizontal gene transfer (HGT). The most abundant GI encodes five homologous small RNAs designated <i>sXFs</i>. RNA sequencing revealed a distinct pattern of noncoding RNAs enriched in EVs, including four island-encoded <i>sXFs</i>. One of the <i>sXF</i>’s stem-loops contains motifs for binding the RNA chaperone Hfq, which is also abundant in EVs. Predicted target analysis suggests that <i>sXFs</i> play a role in regulation of natural competence in bacteria. Additionally, <i>sXF</i> plant target prediction identifies a coiled-coil nucleotide-binding domain leucine-rich repeat receptor (<i>CNL</i>) immune gene that is downregulated following <i>Xf</i> infection and <i>Xf</i>-EV treatment. We propose a model where <i>Xf</i> releases nucleic acid carrying EVs with two functions: one to deliver RNA-related cargo that regulates gene expression in both bacterial and plant cells, and another to deliver DNA-related cargo for the genetic transfer of genomic islands. We highlight island-encoded <i>sXFs</i> as potential virulence factors and vesiduction as a mechanism of HGT of <i>sXFs</i> in <i>Xf</i>. Taken together, our data on <i>Xf</i>-EV cargoes provide a molecular framework for understanding the virulence of <i>Xf</i>.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482278","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":"Cortical Actin Depolymerisation in 3D Cell Culture Enhances Extracellular Vesicle Secretion and Therapeutic Effects","authors":"Zhen Yang,&nbsp;Xiaoke Li,&nbsp;Qiyuan Lin,&nbsp;Fanfan Zhou,&nbsp;Kaini Liang,&nbsp;Jiao Jiao Li,&nbsp;Yudi Niu,&nbsp;Qingchen Meng,&nbsp;Tianyuan Zhao,&nbsp;Hao Li,&nbsp;Du Wang,&nbsp;Jianjing Lin,&nbsp;Hui Li,&nbsp;Bin Wang,&nbsp;Wei Liu,&nbsp;Yanan Du,&nbsp;Jianhao Lin,&nbsp;Dan Xing","doi":"10.1002/jev2.70109","DOIUrl":"https://doi.org/10.1002/jev2.70109","url":null,"abstract":"<p>Three-dimensional (3D) culture systems have been shown to enhance cellular secretion of small extracellular vesicles (sEVs) compared to two-dimensional (2D) culture. However, the molecular mechanisms driving sEV secretion and influencing their potential for disease treatment have not been elucidated. In this study, we discovered the depolymerisation of cortical actin as a new mechanism that leads to increased sEV release, and that in 3D cultured mesenchymal stem cells (MSCs), this process was modulated by the downregulation of integrin-α1 (ITGA1) and subsequent inhibition of the RhoA/cofilin signalling pathway. Interestingly, the knockdown of Rab27A and Rab27B significantly reduced sEV secretion by MSCs to 0.5- and 0.1-fold, respectively. However, there was no difference in expression levels of Rab27A/B between MSCs cultured in 2D and 3D environments. In addition, sEVs derived from 3D cultured MSCs demonstrated enhanced therapeutic function both in vitro and in rat models of osteoarthritis (OA) and wound healing. Collectively, this study illustrates a new mechanism for enhanced secretion of sEVs, involving RhoA/cofilin pathway-dependent cortical actin depolymerisation, which is independent of Rab27A/B. These findings provide novel insights for optimising the yield of stem cell-derived sEVs, as well as their therapeutic efficacy for treating chronic diseases.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482290","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":"The Procoagulant and Fibrinolytic Balance of Extracellular Vesicles Predicts Mortality in Septic Shock Patients","authors":"Romaric Lacroix,&nbsp;Coralie Judicone,&nbsp;Karim Harti Souab,&nbsp;Amandine Bonifay,&nbsp;Anderson Loundou,&nbsp;Tarik Bouriche,&nbsp;Sylvie Cointe,&nbsp;Loris Vallier,&nbsp;Evelyne Abdili,&nbsp;Laurent Arnaud,&nbsp;Stéphane Robert,&nbsp;Philippe Poncelet,&nbsp;Charlotte Grosdidier,&nbsp;Pierre Morange,&nbsp;Eva Cochery-Nouvellon,&nbsp;Sylvie Bouvier,&nbsp;Jean-Christophe Gris,&nbsp;Jean-Yves Lefrant,&nbsp;Marc Leone,&nbsp;Jacques Albanese,&nbsp;Françoise Dignat-George","doi":"10.1002/jev2.70073","DOIUrl":"https://doi.org/10.1002/jev2.70073","url":null,"abstract":"<p>Septic shock is characterised by abnormal coagulation activation with defective fibrinolysis, leading to a high mortality rate. Cellular activation triggers the release of extracellular vesicles (EVs) conveying both procoagulant and fibrinolytic activities. We investigated whether the balance between these activities, termed EV-coagulolytic balance (EV-CLB), predicts day-90 mortality in 225 septic shock patients included in a multicentre prospective study. EV-CLB, quantified as a ratio of TF-dependent thrombin generation to uPA-dependent plasmin generation, was higher in non-survivors than in survivors at 24 h (2.78 [0.86–16.1] a.u. vs. 0.97 [0.34–2.18] a.u., <i>p</i> &lt; 0.001). Moreover, survivors showed a significant decrease in EV-CLB from H0 to H48 in contrast to non-survivors. EV-CLB was a better predictor than EV-associated–procoagulant and -fibrinolytic activities taken individually and better correlated with sepsis severity markers such as SAPS II and lactate levels. Multivariate Cox regression models including severity markers and comorbidities confirmed EV-CLB as an independent predictor of mortality in septic shock patients. Interestingly, subgroup analysis revealed EV-CLB's strong prognostic value in peritonitis, biliary and urinary tract infections and Gram-negative sepsis. Despite challenges in EV measurement requiring technical advancement for clinical translation, EV-CLB represents a potential novel biomarker to guide individualised therapy targeting coagulation/fibrinolysis imbalance in septic shock.</p><p><b>Trial Registration</b>: This trial was registered at ClinicalTrials.gov identifier: NCT02062970</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482277","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":"Programmed Cell Death Protein 10 (PDCD10) Regulates Vesicle Trafficking and Contributes to the Progression of Clear Cell Renal Cell Carcinoma","authors":"Rui Wang,&nbsp;Tianyu Lin,&nbsp;Yi Liu,&nbsp;Hao Wang,&nbsp;Xinyu Liu,&nbsp;Yihan Dong,&nbsp;Jiaxin Li,&nbsp;Huamao Jiang,&nbsp;Ruibing Chen,&nbsp;Yong Wang,&nbsp;Dan Yue","doi":"10.1002/jev2.70108","DOIUrl":"https://doi.org/10.1002/jev2.70108","url":null,"abstract":"<p>Vesicle trafficking is an essential cellular process that plays an important role in tumour progression. Here, we performed a comprehensive transcriptomic and proteomic analysis on 50 clear cell renal cell carcinoma (ccRCC) tumour samples, and the data systematically depicted the alterations in the molecular landscape. Intriguingly, our investigation uncovered profound dysregulation of the vesicle trafficking process. Particularly, PDCD10 was overexpressed in ccRCC, and functional assays showed that PDCD10 promoted cell proliferation, migration and invasion in vitro and enhanced tumour growth in vivo. Additionally, we identified PDCD10 as a critical regulator of endocytosis and exosome secretion. Proteomic analysis of extracellular vesicles (EVs) suggested that PDCD10 overexpression altered the cargo content in EVs and elevated the abundances of cell adhesion and extracellular matrix molecules. Furthermore, Erlotinib treatment impaired PDCD10-induced endocytosis and suppressed cell proliferation and invasion. Collectively, our findings underscore the significance of PDCD10 as a regulator of vesicle trafficking in ccRCC and a potential target for developing novel anticancer therapeutics.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482289","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":"Metabolically Engineered Extracellular Vesicles Released From a Composite Hydrogel Delivery System Regulate the Microenvironment for Periprosthetic Osteolysis Treatment","authors":"Chenchen Wang,&nbsp;Jiang Ju,&nbsp;Chao Fu,&nbsp;Bingbo Bao,&nbsp;Tianhui Ren,&nbsp;Yanan Li,&nbsp;Yuan Wang,&nbsp;Sheng Han,&nbsp;Yuan Wang,&nbsp;Xuan Huang,&nbsp;Hongxing Hu,&nbsp;Xianyou Zheng","doi":"10.1002/jev2.70098","DOIUrl":"https://doi.org/10.1002/jev2.70098","url":null,"abstract":"<p>Despite remarkable progress in total joint arthroplasty, aseptic loosening of titanium (Ti) alloy persists as a critical clinical challenge due to the poor wear resistance and biological inertness of such implants. Targeting of inflammatory osteolysis and remodelling of the osseointegration environment represent promising therapeutic approaches to address this issue. In this study, we developed a novel engineered extracellular vesicles (EVs) with a tag of dextran sulfate (DS-EVs) via metabolic glycan labelling (MGL)-mediated click chemistry. This targeted delivery of EVs, derived from metabolically engineered stem cells, establishes a new cell-free therapeutic system for periprosthetic osteolysis. DS-EVs demonstrated specific macrophage tropism, effectively reprogramming macrophage polarisation from pro-inflammatory M1 to regenerative M2 phenotypes. This phenotypic shift attenuated osteoclastogenesis while enhancing osseointegration through GPC6/Wnt pathway activation in vitro. Furthermore, we designed a multifunctional 3D titanium alloy scaffold with MXene-PVA composite hydrogel coatings (Ti-PPM scaffold). The multifunctional Ti-PPM composite scaffold, incorporating DS-EVs, provides a robust delivery system for periprosthetic osteolysis. This integrated system exhibits dual advantages of enhanced wear resistance and optimised interfacial adhesion, while enabling controlled EV release to maximize DS-EVs' osseointegration potential in vivo. Collectively, our findings establish DS-EVs as a transformative therapeutic modality for periprosthetic osteolysis through dual modulation of the osseointegration microenvironment and macrophage phenotypic heterogeneity.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339590","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 Vesicle Proteome Analysis Improves Diagnosis of Recurrence in Triple-Negative Breast Cancer","authors":"Ju-Yong Hyon,&nbsp;Min Woo Kim,&nbsp;Kyung-A Hyun,&nbsp;Yeji Yang,&nbsp;Seongmin Ha,&nbsp;Jee Ye Kim,&nbsp;Young Kim,&nbsp;Sunyoung Park,&nbsp;Hogyeong Gawk,&nbsp;Heaji Lee,&nbsp;Suji Lee,&nbsp;Sol Moon,&nbsp;Eun Hee Han,&nbsp;Jin Young Kim,&nbsp;Ji Yeong Yang,&nbsp;Hyo-Il Jung,&nbsp;Seung Il Kim,&nbsp;Young-Ho Chung","doi":"10.1002/jev2.70089","DOIUrl":"https://doi.org/10.1002/jev2.70089","url":null,"abstract":"<p>We explored the diagnostic utility of tumor-derived extracellular vesicles (tdEVs) in breast cancer (BC) by performing comprehensive proteomic profiling on plasma samples from 130 BC patients and 40 healthy controls (HC). Leveraging a microfluidic chip-based isolation technique optimized for low plasma volume and effective contaminant depletion, we achieved efficient enrichment of tdEVs. Proteomic analysis identified 26 candidate biomarkers differentially expressed between BC patients and HCs. To enhance biomarker selection robustness, we implemented a hybrid machine learning framework integrating LsBoost, convolutional neural networks, and support vector machines. Among the identified candidates, four EV proteins. ECM1, MBL2, BTD, and RAB5C. not only exhibited strong discriminatory performance, particularly for triple-negative breast cancer (TNBC), but also demonstrated potential relevance to disease recurrence, providing prognostic insights beyond initial diagnosis. Receiver operating characteristic (ROC) curve analysis demonstrated high diagnostic accuracy with an area under the curve (AUC) of 0.924 for BC and 0.973 for TNBC, as determined by mass spectrometry. These findings were further substantiated by immuno assay validation, which yielded an AUC of 0.986 for TNBC. Collectively, our results highlight the potential of EV proteomics as a minimally invasive, blood-based platform for both accurate detection and recurrence risk stratification in breast cancer and its aggressive subtypes, offering promising implications for future clinical applications.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339544","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":"Clinical Scale MSC-Derived Extracellular Vesicles Enhance Poststroke Neuroplasticity in Rodents and Non-Human Primates","authors":"Eun Hee Kim,&nbsp;Jeong Pyo Son,&nbsp;Gyun Sik Oh,&nbsp;Suji Park,&nbsp;Eunchong Hong,&nbsp;Kyoung-Sun Lee,&nbsp;Michael Chopp,&nbsp;Oh Young Bang","doi":"10.1002/jev2.70110","DOIUrl":"https://doi.org/10.1002/jev2.70110","url":null,"abstract":"<p>Stroke is a leading cause of death and disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) has shown considerable promise in rodent models of stroke. However, the therapeutic efficacy and safety of clinical-scale MSC-EVs for ischemic stroke are not well elucidated, especially in non-human primates. We developed a scalable production method for MSC-EVs using a 3D bioprocessing platform. EVs were isolated with a filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, nanoflow cytometry analysis, proteomic and lipidomic analysis using mass spectrometry, and RNA sequencing. We determined the appropriate dosage and frequency of intravenous administration of EVs in a mouse stroke model. A biodistribution study of the selected dose regimen was performed using the internal cargo of EVs, human mitochondrial DNA. We then confirmed the efficacy of EVs in a marmoset stroke model. Improvement in behavioural tests and MRI-based neuroplasticity were compared between the control and EV groups through blinded evaluation. The proteome profiles of the infarcted hemisphere were also evaluated. EV products showed suitable lot-to-lot consistency. In a mouse stroke model, intravenous administration of a dose of 6 × 10⁸ EVs for 5 days resulted in the smallest infarct volume and improvement in motor function. A biodistribution study showed that EVs were rapidly distributed into systemic organs and were relatively specifically distributed to the infarcted brain areas. Intravenous administration of an equivalent dose (3.5 × 10⁹ EVs for 5 days) in a marmoset stroke model significantly improved motor functions and anatomical connectivity on diffusion MRI, and significantly reduced infarct volume. Proteomics analyses indicated that EV treatment promoted neurogenesis, synapse organization, and vascular development. In conclusion, this study is the first to demonstrate that a clinical-scale EV product is safe and significantly enhances function recovery and neuroplasticity in a non-human primate stroke model, offering a promising treatment for human stroke.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339670","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":"Engineered Mesenchymal Stem Cell–Derived Extracellular Vesicles Reverse Endothelial–Mesenchymal Transition in Atherosclerosis","authors":"Zhuo Chen,&nbsp;Kai Chang,&nbsp;Sha Yang,&nbsp;Ruijia Deng,&nbsp;Yuan He,&nbsp;Ligai Zhang,&nbsp;Ming Chen,&nbsp;Dingqun Bai,&nbsp;Yan Pi","doi":"10.1002/jev2.70099","DOIUrl":"https://doi.org/10.1002/jev2.70099","url":null,"abstract":"<p>Endothelial–mesenchymal transition (EndMT) of vascular endothelial cells (VECs) plays a pivotal role in the progression of atherosclerosis (AS). The therapeutic potential of reversing EndMT holds promise for AS treatment. In this study, bone marrow mesenchymal stem cells (BMSCs)–derived extracellular vesicles (EVs) are engineered as nanostructured drug carriers with two functional modules, targeting module and functional protein module. In targeting module, to specifically target VECs, the cholesterol-modified aptamers of VECs-specific protein vascular endothelial growth factor (VEGF) are assembled to the engineered EVs. In functional protein module, engineered EVs are infected with recombinant silent information regulator 2–related enzyme 1 (SIRT1) adenoviruses, with the achievement of SIRT1 protein overexpression on the surface. Upon targeted aggregation around the mesenchymalized VECs, the engineered EVs are taken up by VECs and the loaded SIRT1 is released into VECs. Then, SIRT1 can effectively reverse VECs-EndMT by activating nuclear factor-erythroid 2–related factor 2 (Nrf2) and regulating oxidative stress response. The targeted efficacy for precision therapy in AS has been successfully demonstrated both in vitro and in vivo, by reversing EndMT and reducing inflammation in atherosclerotic plaques. This study provides a novel strategy for AS treatment and offers insights into the next generation of regenerative medicine technologies based on engineered EVs.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339542","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 Prostate Cancer-Corrupted Osteoclasts Drive a Chain Reaction of Inflammatory Osteolysis and Tumour Progression at the Bone Metastatic Site","authors":"Takaaki Tamura,&nbsp;Tomofumi Yamamoto,&nbsp;Akiko Kogure,&nbsp;Yusuke Yoshioka,&nbsp;Yusuke Yamamoto,&nbsp;Shinichi Sakamoto,&nbsp;Tomohiko Ichikawa,&nbsp;Takahiro Ochiya","doi":"10.1002/jev2.70091","DOIUrl":"https://doi.org/10.1002/jev2.70091","url":null,"abstract":"<p>Advanced-stage prostate cancer (PCa) frequently causes bone metastases, resulting in a poor prognosis and a 5-year survival rate of 30%. PCa bone metastasis is a highly complex and fluctuating process, comprising of osteolytic (bone-degrading) and osteogenic (bone-forming) lesions. Although this system is mainly controlled by alterations in the receptor activator of NF-κB ligand (RANKL), RANKL-based treatment does not prolong the overall survival of patients with PCa bone metastasis. Therefore, it is essential to understand the other interactions between tumour cells and bone-resident cells in the metastatic niche to develop novel treatments. Extracellular vesicles (EVs) play key roles in intercellular communication and actively function in the bone microenvironment. We report that PCa cells corrupt osteoclasts (OCs) via their secretomes, inducing a pathological phenotype. EVs from pathological OCs activate bone-resorbing OCs and suppress bone-forming osteoblasts (OBs), leading to bone destruction. Pathological OCs increased IL-1β secretion and produced EVs with miR-5112 and miR-1963, targeting <i>Parp1</i> in OCs and <i>Hoxa1</i> in OBs. This led to OC maturation and IL-1β secretion, and inhibited OB mineralization. Injection of these miRNAs in vivo promoted PCa metastasis-disrupting bone. We report the mediation of EVs from OCs under pathological conditions that modulate the bone metastatic niche independently of RANKL.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339543","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":"Macrophages Internalize Epithelial-Derived Extracellular Vesicles That Contain Ferritin via the Macrophage Scavenger Receptor 1 to Promote Inflammatory Bowel Disease","authors":"Wenxin Zhang,&nbsp;Weichen Dong,&nbsp;Chen Cheng,&nbsp;Hongting Zhao,&nbsp;Yutong Liu,&nbsp;Kristina Zaydel,&nbsp;Liora Frech,&nbsp;Zhiyao Xing,&nbsp;Wusheng Zhu,&nbsp;Bing Zhou,&nbsp;Yi Li,&nbsp;Esther G. Meyron-Holtz,&nbsp;Kuanyu Li","doi":"10.1002/jev2.70105","DOIUrl":"https://doi.org/10.1002/jev2.70105","url":null,"abstract":"<p>The incidence of inflammatory bowel disease (IBD) is on the rise, yet current clinical treatments are limited. Previous studies have identified impairments in both systemic and local iron metabolism in IBD patients. However, the impact of iron dyshomeostasis on the development and pathogenesis of IBD remains elusive. In this study, we confirmed iron deposition in inflamed intestinal lesions of IBD patients and mice with DSS-induced colitis, accompanied by distinct distribution patterns of the iron storage protein ferritin. To reveal the role of ferritin in the involvement of pathology of IBD, we constructed intestinal epithelial cell- or myeloid-specific ferritin H (<i>FtH</i>) knockout mice and demonstrated that intestinal epithelial cells (IECs) release extracellular vesicles (EVs) that contain iron-loaded ferritin. These EVs are internalized by macrophages via the macrophage scavenger receptor 1 (Msr1), leading to the activation of inflammatory responses and oxidative stress, thereby exacerbating colitis severity. Genetic deletion of <i>FtH</i> in IECs or blockage of macrophage ferritin uptake, either through Msr1 inhibitor fucoidan or through <i>Msr1</i> knockdown (KD), suppressed inflammatory symptoms. Thus, EVs containing iron-loaded ferritin released from IECs activate macrophages and contribute to IBD development, supporting that IBD patients with iron deficiency anaemia are often prescribed iron supplementation in a remission phase, other than in an active phase of the disease. Pharmacological inhibition of this ferritin secretion and engulfing process provides a therapeutic target for the disease.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"14 6","pages":""},"PeriodicalIF":15.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339669","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}