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Small RNAs in plasma extracellular vesicles define biomarkers of premanifest changes in Huntington's disease 血浆细胞外囊泡中的小 RNA 确定了亨廷顿氏病发病前变化的生物标志物。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-10-08 DOI: 10.1002/jev2.12522
Marina Herrero-Lorenzo, Jesús Pérez-Pérez, Georgia Escaramís, Saül Martínez-Horta, Rocío Pérez-González, Elisa Rivas-Asensio, Jaime Kulisevsky, Ana Gámez-Valero, Eulàlia Martí

Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV-sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF-Glu-CTC, tRF-Gly-GCC, miR-451a, miR-21-5p, miR-26a-5p, miR-27a-3p and let7a-5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR-21-5p was significantly decreased over time in a longitudinal study; and miR-21-5p and miR-26a-5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV-sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage.

尽管对亨廷顿氏病(Huntington's disease,HD)的认识取得了进展,但在功能衰退之前的疾病临床前阶段,仍需要分子生物标志物对突变携带者进行分类。小 RNA(sRNA)是一种很有前景的生物标志物,因为它们的表达水平对病理生物学过程高度敏感。在这里,我们使用优化的血浆细胞外囊泡(EVs)纯化方法和详尽的 sRNA 测序数据分析流水线,证明了 EV-sRNAs 在突变携带者中的早期下调,而且这种下调与显现前的认知表现相关。我们在更多受试者中验证了七个候选 sRNA(tRF-Glu-CTC、tRF-Gly-GCC、miR-451a、miR-21-5p、miR-26a-5p、miR-27a-3p 和 let7a-5p),结果显示它们在发病前阶段具有显著的诊断准确性。其中,在一项纵向研究中,miR-21-5p 随着时间的推移显著下降;miR-21-5p 和 miR-26a-5p 的水平与躁狂症前期人群的认知变化相关。总之,本研究结果表明,血浆 EV-sRNA 的失调是突变携带者的早期生物特征,其特定种类突出显示了突变前阶段的进展和认知变化。
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引用次数: 0
A critical systematic review of extracellular vesicle clinical trials 细胞外囊泡临床试验批判性系统回顾
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-27 DOI: 10.1002/jev2.12510
Rachel R. Mizenko, Madison Feaver, Batuhan T. Bozkurt, Neona Lowe, Bryan Nguyen, Kuan-Wei Huang, Aijun Wang, Randy P. Carney

This systematic review examines the landscape of extracellular vesicle (EV)-related clinical trials to elucidate the field's trends in clinical applications and EV-related methodologies, with an additional focus on the acknowledgement of EV subpopulations. By analysing data from public reporting repositories, we catalogued 471 EV-related clinical trials to date, with indications for over 200 diseases. Diagnostics and companion diagnostics represented the bulk of EV-related clinical trials with cancer being the most frequent application. EV-related therapeutics trials mainly utilized mesenchymal stromal cell (MSC) EVs and were most frequently used for treatment of respiratory illnesses. Ultracentrifugation and RNA-sequencing were the most common isolation and characterization techniques; however, methodology for each was not frequently reported in study records. Most of the reported characterization relied on bulk characterization of EV isolates, with only 11% utilizing EV subpopulations in their experimental design. While this may be connected to a lack of available techniques suitable for clinical implementation, it also highlights the opportunity for use of EV subpopulations to improve translational efforts. As academic research identifies more chemically distinct subpopulations and technologies for their enrichment, we forecast to more refined EV trials in the near future. This review emphasizes the need for meticulous methodological reporting and consideration of EV subpopulations to enhance the translational success of EV-based interventions, pointing towards a paradigm shift in personalized medicine.

这篇系统性综述研究了细胞外囊泡 (EV) 相关临床试验的情况,以阐明该领域在临床应用和 EV 相关方法方面的趋势,并重点关注 EV 亚群的认可情况。通过分析来自公共报告库的数据,我们对迄今为止的 471 项 EV 相关临床试验进行了编目,涉及 200 多种疾病的适应症。诊断和辅助诊断占 EV 相关临床试验的大部分,其中癌症是最常见的应用。EV相关治疗试验主要利用间充质基质细胞(MSC)EV,最常用于治疗呼吸系统疾病。超速离心和RNA测序是最常见的分离和表征技术;然而,研究记录中并没有经常报告每种技术的方法。大多数报告的表征方法都依赖于EV分离物的批量表征,只有11%的研究在实验设计中利用了EV亚群。虽然这可能与缺乏适合临床应用的可用技术有关,但也凸显了利用 EV 亚群改进转化工作的机会。随着学术研究发现更多化学性质截然不同的亚群及其富集技术,我们预测在不久的将来会有更精细的 EV 试验。这篇综述强调了细致的方法学报告和考虑 EV 亚群的必要性,以提高基于 EV 的干预措施的转化成功率,并指出了个性化医学的范式转变。
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引用次数: 0
Integrin α6-containing extracellular vesicles promote lymphatic remodelling for pre-metastatic niche formation in lymph nodes via interplay with CD151 含整合素α6的细胞外小泡通过与CD151的相互作用促进淋巴重塑,从而在淋巴结中形成转移前的龛位
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-27 DOI: 10.1002/jev2.12518
Yan Lin, Hanhao Zheng, Linpei Jia, Yuming Luo, Dingwen Zhang, Mingjie An, Mingrui Pang, Xiayao Diao, Wenjie Li, Jiancheng Chen, Yuanlong Li, Daiyin Liu, Zhicong Liu, Jian Huang, Tianxin Lin, Changhao Chen

Heterogeneous extracellular vesicles (EVs) from various types of tumours are acknowledged for inducing the formation of pre-metastatic “niches” in draining lymph nodes (LNs) to promote lymphatic metastasis. In order to identify the specific subpopulations of EVs involved, we performed high-resolution proteomic analysis combined with nanoflow cytometry of bladder cancer (BCa) tissue-derived EVs to identify a novel subset of tumour-derived EVs that contain integrin α6 (ITGA6+EVs) and revealed the positive correlation of ITGA6+EVs with the formation of pre-metastatic niche in draining LNs and lymphatic metastasis in multicentre clinical analysis of 820-case BCa patients. BCa-derived ITGA6+EVs induced E-selectin (SELE)-marked lymphatic remodelling pre-metastatic niche and promoted metastasis in draining LNs through delivering cargo circRNA-LIPAR to lymphatic endothelial cells in vivo and in vitro. Mechanistically, LIPAR linked ITGA6 to the switch II domain of RAB5A and sustained RAB5A GTP-bound activated state, thus maintaining the production of ITGA6+EVs loaded with LIPAR through endosomal trafficking. ITGA6+EVs targeted lymphatic vessels through ITGA6-CD151 interplay and released LIPAR to induce SELE overexpression-marked lymphatic remodelling pre-metastatic niche. Importantly, we constructed engineered-ITGA6 EVs to inhibit lymphatic pre-metastatic niche, which suppressed lymphatic metastasis and prolonged survival in preclinical models. Collectively, our study uncovers the mechanism of BCa-derived ITGA6+EVs mediating pre-metastatic niche and provides an engineered-EV-based strategy against BCa lymphatic metastasis.

来自各种类型肿瘤的异质性细胞外囊泡(EVs)被认为可诱导引流淋巴结(LNs)形成转移前 "壁龛",从而促进淋巴转移。为了确定参与其中的特定 EVs 亚群、我们对膀胱癌(BCa)组织衍生的EVs进行了高分辨率蛋白质组学分析,并结合纳米流式细胞术鉴定出含有整合素α6(ITGA6+EVs)的新型肿瘤衍生EVs亚群,并在对820例BCa患者的多中心临床分析中揭示了ITGA6+EVs与引流淋巴结中转移前壁龛的形成和淋巴转移的正相关性。BCa衍生的ITGA6+EVs在体内和体外通过向淋巴内皮细胞输送货物circRNA-LIPAR,诱导E-选择素(SELE)标记的淋巴重塑转移前生态位,并促进引流LN的转移。从机理上讲,LIPAR将ITGA6与RAB5A的开关II结构域连接起来,并维持RAB5A的GTP结合活化状态,从而通过内体运输维持负载LIPAR的ITGA6+EV的产生。ITGA6+EVs 通过 ITGA6-CD151 相互作用靶向淋巴管并释放 LIPAR,从而诱导 SELE 过表达标记的淋巴重塑转移前龛位。重要的是,我们构建了工程化-ITGA6 EVs 来抑制淋巴转移前生态位,从而抑制了淋巴转移并延长了临床前模型的生存期。总之,我们的研究揭示了来源于BCa的ITGA6+EVs介导转移前生态位的机制,并提供了一种基于工程化EV的抗BCa淋巴转移策略。
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引用次数: 0
MAP kinase kinase 1 (MEK1) within extracellular vesicles inhibits tumour growth by promoting anti-tumour immunity 细胞外囊泡中的 MAP 激酶激酶 1 (MEK1) 通过促进抗肿瘤免疫抑制肿瘤生长
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-27 DOI: 10.1002/jev2.12515
Stephen C. Searles, Wei-Shan Chen, Jarrod D. Yee, Preston Lee, Calvin K. Lee, Christine Caron, Felippe Neto, Irina Matei, David Lyden, Jack D. Bui

Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized. Using a mouse model of highly immunogenic regressor versus poorly immunogenic progressor tumour cells, we have characterized the role of EVs in activating macrophages and promoting tumour rejection. We found that the signalling molecule MAP2K1 (MEK1) is enriched in EVs secreted by regressor relative to progressor cells. Progressor EVs engineered to have levels of MEK1 similar to regressor EVs could inhibit tumour growth by indirectly promoting adaptive immunity in both syngeneic and 3rd party tumours. This effect required MEK1 activity and could occur by activating macrophages to promote adaptive immune responses against the tumour via the cytokine interferon-gamma. Our results suggest that MEK inhibition may be deleterious to cancer treatment, since MEK1 plays an important cell-extrinsic, tumour-suppressive role within EVs. Moreover, the delivery of MEK1 to tumour-associated macrophages, either by EVs, nanoparticles, or some other means, could be a useful strategy to treat cancer via the activation of anti-tumour immunity.

细胞外囊泡(EVs)在许多生理过程中介导细胞间的交流,并能调节癌症患者的免疫反应。有关癌症中 EVs 的大多数研究都集中在它们的肿瘤促进特性上。除了携带抗原之外,EVs 是否以及如何介导肿瘤消退还没有很好的定性。我们利用小鼠高免疫原性回归细胞和低免疫原性进展细胞模型,研究了 EVs 在激活巨噬细胞和促进肿瘤排斥反应中的作用。我们发现,相对于进展期细胞,抑制期细胞分泌的EV中富含信号分子MAP2K1(MEK1)。经过改造的进展期EV的MEK1水平与回归期EV相似,可以通过间接促进自体和第三方肿瘤的适应性免疫来抑制肿瘤生长。这种效应需要 MEK1 的活性,并可能通过激活巨噬细胞来实现,从而通过细胞因子干扰素-γ 促进针对肿瘤的适应性免疫反应。我们的研究结果表明,MEK 抑制可能对癌症治疗有害,因为 MEK1 在 EVs 中发挥着重要的细胞外抑制肿瘤作用。此外,通过EV、纳米颗粒或其他方式将MEK1传递给肿瘤相关巨噬细胞,可能是一种通过激活抗肿瘤免疫力治疗癌症的有效策略。
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引用次数: 0
Beyond basic characterization and omics: Immunomodulatory roles of platelet-derived extracellular vesicles unveiled by functional testing 超越基础表征和全息图学:通过功能测试揭示血小板源性细胞外囊泡的免疫调节作用
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-27 DOI: 10.1002/jev2.12513
Mari Palviainen, Johanna Puutio, Rikke Halse Østergaard, Johannes A. Eble, Katariina Maaninka, Umar Butt, Joseph Ndika, Otto K. Kari, Masood Kamali-Moghaddam, Kasper Kjaer-Sorensen, Claus Oxvig, Ana M. Aransay, Juan M. Falcon-Perez, Antonio Federico, Dario Greco, Saara Laitinen, Yuya Hayashi, Pia R.-M. Siljander

Renowned for their role in haemostasis and thrombosis, platelets are also increasingly recognized for their contribution in innate immunity, immunothrombosis and inflammatory diseases. Platelets express a wide range of receptors, which allows them to reach a variety of activation endpoints and grants them immunomodulatory functions. Activated platelets release extracellular vesicles (PEVs), whose formation and molecular cargo has been shown to depend on receptor-mediated activation and environmental cues.

This study compared the immunomodulatory profiles of PEVs generated via activation of platelets by different receptors, glycoprotein VI, C-type lectin-like receptor 2 and combining all thrombin-collagen receptors. Functional assays in vivo in zebrafish and in vitro in human macrophages highlighted distinct homing and secretory responses triggered by the PEVs. In contrast, omics analyses of protein and miRNA cargo combined with physicochemical particle characterization found only subtle differences between the activated PEV types, which were insufficient to predict their different immunomodulatory functions. In contrast, constitutively released PEVs, formed in the absence of an exogenous activator, displayed a distinct immunomodulatory profile from the receptor-induced PEVs.

Our findings underscore that PEVs are tunable through receptor-mediated activation. To truly comprehend their role(s) in mediating platelet functions among immune cells, conducting functional assays is imperative.

血小板因其在止血和血栓形成中的作用而闻名于世,但其在先天性免疫、免疫血栓形成和炎症疾病中的贡献也日益得到认可。血小板表达多种受体,这使它们能够达到各种活化终点,并赋予它们免疫调节功能。本研究比较了不同受体(糖蛋白 VI、C 型凝集素样受体 2 和所有凝血酶-胶原受体)激活血小板后产生的 PEVs 的免疫调节特征。在斑马鱼体内和人类巨噬细胞体外进行的功能测试突出显示了 PEV 所引发的不同的归巢和分泌反应。与此相反,蛋白质和 miRNA 货物的全局分析结合颗粒的物理化学特征发现,活化的 PEV 类型之间只有细微差别,不足以预测其不同的免疫调节功能。与此相反,在没有外源激活剂的情况下形成的组成型释放 PEV 与受体诱导的 PEV 显示出不同的免疫调节特征。我们的发现强调了 PEV 可通过受体介导的激活进行调节。要真正理解 PEV 在免疫细胞中介导血小板功能的作用,必须进行功能测试。
{"title":"Beyond basic characterization and omics: Immunomodulatory roles of platelet-derived extracellular vesicles unveiled by functional testing","authors":"Mari Palviainen,&nbsp;Johanna Puutio,&nbsp;Rikke Halse Østergaard,&nbsp;Johannes A. Eble,&nbsp;Katariina Maaninka,&nbsp;Umar Butt,&nbsp;Joseph Ndika,&nbsp;Otto K. Kari,&nbsp;Masood Kamali-Moghaddam,&nbsp;Kasper Kjaer-Sorensen,&nbsp;Claus Oxvig,&nbsp;Ana M. Aransay,&nbsp;Juan M. Falcon-Perez,&nbsp;Antonio Federico,&nbsp;Dario Greco,&nbsp;Saara Laitinen,&nbsp;Yuya Hayashi,&nbsp;Pia R.-M. Siljander","doi":"10.1002/jev2.12513","DOIUrl":"https://doi.org/10.1002/jev2.12513","url":null,"abstract":"<p>Renowned for their role in haemostasis and thrombosis, platelets are also increasingly recognized for their contribution in innate immunity, immunothrombosis and inflammatory diseases. Platelets express a wide range of receptors, which allows them to reach a variety of activation endpoints and grants them immunomodulatory functions. Activated platelets release extracellular vesicles (PEVs), whose formation and molecular cargo has been shown to depend on receptor-mediated activation and environmental cues.</p><p>This study compared the immunomodulatory profiles of PEVs generated via activation of platelets by different receptors, glycoprotein VI, C-type lectin-like receptor 2 and combining all thrombin-collagen receptors. Functional assays in vivo in zebrafish and in vitro in human macrophages highlighted distinct homing and secretory responses triggered by the PEVs. In contrast, omics analyses of protein and miRNA cargo combined with physicochemical particle characterization found only subtle differences between the activated PEV types, which were insufficient to predict their different immunomodulatory functions. In contrast, constitutively released PEVs, formed in the absence of an exogenous activator, displayed a distinct immunomodulatory profile from the receptor-induced PEVs.</p><p>Our findings underscore that PEVs are tunable through receptor-mediated activation. To truly comprehend their role(s) in mediating platelet functions among immune cells, conducting functional assays is imperative.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":"13 10","pages":""},"PeriodicalIF":15.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.12513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324729","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}
引用次数: 0
Scalable production of siRNA-encapsulated extracellular vesicles for the inhibition of KRAS-mutant cancer using acoustic shock waves 利用声波冲击波大规模生产用于抑制 KRAS 突变癌症的 siRNA 包裹细胞外囊泡
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-26 DOI: 10.1002/jev2.12508
Hyo Kyeong Kim, Yujeong Choi, Kyoung Hwa Kim, Yeongju Byun, Tae Hee Kim, Jae Hwan Kim, Shung Hyun An, DaeHo Bae, Myeong Kwan Choi, Minyoung Lee, Gwansuk Kang, Jihwa Chung, Seok-Hyun Kim, Kihwan Kwon

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel “shock wave extracellular vesicles engineering technology” (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.

细胞外囊泡(EVs)已成为一种潜在的核酸类治疗药物递送载体,但其大规模生产和货物装载效率方面的挑战限制了其治疗潜力。为了解决这些问题,我们开发了一种新颖的 "冲击波细胞外囊泡工程技术"(SWEET),作为一种非遗传、可扩展的生产策略,利用冲击波(SWs)将 siRNA 封装在 EVs 中。在这里,我们描述了如何利用 SWEET 平台将大量 KRASG12C 靶向 siRNA 高效地装载到小型牛乳衍生 EVs(sBMEVs)中。加载了 siRNA 的 sBMEVs 能有效抑制癌细胞中致癌基因 KRASG12C 的表达;在非小细胞肺癌异种移植小鼠模型中静脉注射这些 siRNA 能抑制肿瘤生长。我们的研究表明,SWEET 平台有可能成为一种新方法,大规模生产载货 EVs,用于广泛的治疗应用。
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引用次数: 0
Benchmarking transcriptome deconvolution methods for estimating tissue- and cell-type-specific extracellular vesicle abundances 用于估算组织和细胞类型特异性细胞外囊泡丰度的转录组去卷积方法基准测试
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-25 DOI: 10.1002/jev2.12511
Jannik Hjortshøj Larsen, Iben Skov Jensen, Per Svenningsen

Extracellular vesicles (EVs) contain cell-derived lipids, proteins and RNAs; however, determining the tissue- and cell-type-specific EV abundances in body fluids remains a significant hurdle for our understanding of EV biology. While tissue- and cell-type-specific EV abundances can be estimated by matching the EV's transcriptome to a tissue's/cell type's expression signature using deconvolutional methods, a comparative assessment of deconvolution methods' performance on EV transcriptome data is currently lacking. We benchmarked 11 deconvolution methods using data from four cell lines and their EVs, in silico mixtures, 118 human plasma and 88 urine EVs. We identified deconvolution methods that estimated cell type-specific abundances of pure and in silico mixed cell line-derived EV samples with high accuracy. Using data from two urine EV cohorts with different EV isolation procedures, four deconvolution methods produced highly similar results. The three methods were also concordant in their tissue- and cell-type-specific plasma EV abundance estimates. We identified driving factors for deconvolution accuracy and highlighted the importance of implementing biological knowledge in creating the tissue/cell type signature. Overall, our analyses demonstrate that the deconvolution algorithms DWLS and CIBERSORTx produce highly similar and accurate estimates of tissue- and cell-type-specific EV abundances in biological fluids.

细胞外囊泡(EV)含有细胞衍生的脂质、蛋白质和 RNA;然而,确定体液中组织和细胞类型特异的 EV 丰度仍然是我们了解 EV 生物学的一个重大障碍。虽然组织和细胞类型特异性的 EV 丰度可以通过使用去卷积方法将 EV 的转录组与组织/细胞类型的表达特征相匹配来估算,但目前还缺乏对去卷积方法在 EV 转录组数据上的性能的比较评估。我们使用来自四种细胞系及其 EV、硅学混合物、118 人血浆和 88 尿液 EV 的数据,对 11 种去卷积方法进行了基准测试。我们确定了一些去卷积方法,这些方法能高精度地估算纯细胞系和硅学混合细胞系衍生 EV 样本的细胞类型特异性丰度。使用来自两个尿液EV队列的数据和不同的EV分离程序,四种解卷积方法得出了高度相似的结果。这三种方法对组织和细胞类型特异性血浆 EV 丰度的估计也是一致的。我们确定了去卷积准确性的驱动因素,并强调了在创建组织/细胞类型特征时应用生物学知识的重要性。总之,我们的分析表明,解卷积算法 DWLS 和 CIBERSORTx 对生物液体中组织和细胞类型特异性 EV 丰度的估计高度相似且准确。
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引用次数: 0
Extracellular vesicles derived from melanoma cells induce carcinoma-associated fibroblasts via miR-92b-3p mediated downregulation of PTEN 来自黑色素瘤细胞的细胞外囊泡通过 miR-92b-3p 介导的 PTEN 下调诱导癌相关成纤维细胞。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-24 DOI: 10.1002/jev2.12509
Stefanie Kewitz-Hempel, Nicola Windisch, Gerd Hause, Lutz Müller, Cord Sunderkötter, Dennis Gerloff

In melanoma, carcinoma-associated fibroblasts (CAFs) are important cellular components in the tumour microenvironment due to their potential to promote tumour growth and metastatic spread of malignant cells. Melanoma cells have the ability to affect non-tumour cells in the microenvironment by releasing extracellular vesicles (EVs). The mechanisms responsible for reprogramming normal dermal fibroblasts (NHDFs) into CAFs remain incompletely understood. However, it is likely thought to be mediated by melanoma-specific miRNAs, which are transported by EVs derived from melanoma cells. Therefore, we wondered if one of the most enriched miRNAs in EVs secreted by melanoma cells, miR-92b-3p, is involved in the conversion of normal fibroblasts into CAFs. We observed that melanoma cell-derived EVs indeed delivered miR-92b-3p into NHDFs and that its accumulation correlated with CAF formation, as demonstrated by enhanced expression of CAF marker genes and increased proliferation and migration. Overexpression of miR-92b-3p in NHDFs revealed similar results, while EVs deficient of miR-92b-3p did not induce a CAF phenotype. As a target we identified PTEN, whose repression led to increased expression of CAF markers. We thus provide a novel pathway of intercellular communication by which melanoma cells control the transformation of CAFs by virtue of EV-transported miRNAs.

在黑色素瘤中,癌相关成纤维细胞(CAFs)是肿瘤微环境中的重要细胞成分,因为它们具有促进肿瘤生长和恶性细胞转移扩散的潜力。黑色素瘤细胞能够通过释放细胞外囊泡 (EV) 影响微环境中的非肿瘤细胞。将正常真皮成纤维细胞(NHDFs)重编程为 CAFs 的机制尚不完全清楚。不过,人们认为这可能是由黑色素瘤特异性 miRNAs 介导的,而这些 miRNAs 是由黑色素瘤细胞的 EVs 运输的。因此,我们想知道黑色素瘤细胞分泌的EVs中最富集的miRNA之一miR-92b-3p是否参与了正常成纤维细胞向CAFs的转化。我们观察到,黑色素瘤细胞衍生的EV确实将miR-92b-3p传递到了NHDFs中,其积累与CAF的形成有关,这表现在CAF标记基因的表达增强、增殖和迁移增加。在NHDFs中过表达miR-92b-3p也显示了类似的结果,而缺乏miR-92b-3p的EVs不会诱导CAF表型。我们确定了 PTEN 作为靶点,它的抑制会导致 CAF 标志物的表达增加。因此,我们提供了一种新的细胞间通信途径,黑色素瘤细胞通过 EV 运送的 miRNA 控制 CAF 的转化。
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引用次数: 0
Enhancing protective immunity against bacterial infection via coating nano-Rehmannia glutinosa polysaccharide with outer membrane vesicles 通过外膜囊泡包裹纳米地黄多糖,增强对细菌感染的保护性免疫。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-24 DOI: 10.1002/jev2.12514
Yee Huang, Jiaying Sun, Xuemei Cui, Xuefeng Li, Zizhe Hu, Quanan Ji, Guolian Bao, Yan Liu

With the coming of the post-antibiotic era, there is an increasingly urgent need for safe and efficient antibacterial vaccines. Bacterial outer membrane vesicles (OMVs) have received increased attention recently as a potential subunit vaccine. OMVs are non-replicative and contain the principle immunogenic bacterial antigen, which circumvents the safety concerns of live-attenuated vaccines. Here, we developed a novel nano-vaccine by coating OMVs onto PEGylated nano-Rehmannia glutinosa polysaccharide (pRL) in a structure consisting of concentric circles, resulting in a more stable vaccine with improved immunogenicity. The immunological function of the pRL-OMV formulation was evaluated in vivo and in vitro, and the underlying mechanism was studied though transcriptomic analysis. The pRL-OMV formulation significantly increased dendritic cell (DC) proliferation and cytokine secretion. Efficient phagocytosis of the formulation by DCs was accompanied by DC maturation. Further, the formulation demonstrated superior lymph node targeting, contributing to a potent mixed cellular response and bacterial-specific antibody response against Bordetella bronchiseptica infection. Specifically, transcriptomic analysis revealed that the immune protection function correlated with T-cell receptor signalling and Th1/Th2/Th17 differentiation, among other markers of enhanced immunological activity. These findings have implications for the future application of OMV-coated nano-carriers in antimicrobial immunotherapy.

随着后抗生素时代的到来,人们对安全高效的抗菌疫苗的需求日益迫切。作为一种潜在的亚单位疫苗,细菌外膜囊泡 (OMV) 近来受到越来越多的关注。OMVs 不具有复制性,含有主要的免疫原性细菌抗原,从而避免了减毒活疫苗的安全性问题。在此,我们开发了一种新型纳米疫苗,将 OMV 包覆在 PEG 化纳米地黄多糖(pRL)上,形成同心圆结构,从而获得了一种更稳定、免疫原性更强的疫苗。我们在体内和体外评估了 pRL-OMV 配方的免疫功能,并通过转录组分析研究了其潜在机制。pRL-OMV制剂显著增加了树突状细胞(DC)的增殖和细胞因子的分泌。DC对制剂的高效吞噬伴随着DC的成熟。此外,该制剂还表现出卓越的淋巴结靶向性,有助于产生针对支气管败血波氏杆菌感染的强效混合细胞反应和细菌特异性抗体反应。具体来说,转录组分析表明,免疫保护功能与 T 细胞受体信号传导和 Th1/Th2/Th17 分化以及其他免疫活性增强的标记相关。这些发现对未来在抗菌免疫疗法中应用 OMV 涂层纳米载体具有重要意义。
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引用次数: 0
Plasma-derived extracellular vesicles (EVs) as biomarkers of sepsis in burn patients via label-free Raman spectroscopy 通过无标记拉曼光谱将血浆源性细胞外囊泡 (EV) 作为烧伤患者败血症的生物标记物
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-09-19 DOI: 10.1002/jev2.12506
Hannah J. O'Toole, Neona M. Lowe, Vishalakshi Arun, Anna V. Kolesov, Tina L. Palmieri, Nam K. Tran, Randy P. Carney

Sepsis following burn trauma is a global complication with high mortality, with ∼60% of burn patient deaths resulting from infectious complications. Diagnosing sepsis is complicated by confounding clinical manifestations of the burn injury, and current biomarkers lack the sensitivity and specificity required for prompt treatment. There is a strong rationale to assess circulating extracellular vesicles (EVs) from patient liquid biopsy as sepsis biomarkers due to their release by pathogens from bacterial biofilms and roles in the subsequent immune response. This study applies Raman spectroscopy to patient plasma-derived EVs for rapid, sensitive, and specific detection of sepsis in burn patients, achieving 97.5% sensitivity and 90.0% specificity. Furthermore, spectral differences between septic and non-septic burn patient EVs could be traced to specific glycoconjugates of bacterial strains associated with sepsis morbidity. This work illustrates the potential application of EVs as biomarkers in clinical burn trauma care and establishes Raman analysis as a fast, label-free method to specifically identify features of bacterial EVs relevant to infection amongst the host background.

烧伤创伤后败血症是一种全球性并发症,死亡率很高,60%的烧伤患者死于感染并发症。脓毒症的诊断因烧伤的临床表现而变得复杂,目前的生物标志物缺乏及时治疗所需的灵敏度和特异性。由于病原体从细菌生物膜中释放出细胞外囊泡 (EV),并在随后的免疫反应中发挥作用,因此将患者液体生物样本中的循环细胞外囊泡 (EV) 作为败血症生物标志物进行评估具有很强的合理性。本研究将拉曼光谱应用于患者血浆中的 EVs,以快速、灵敏、特异地检测烧伤患者的败血症,灵敏度达 97.5%,特异度达 90.0%。此外,脓毒症和非脓毒症烧伤患者 EVs 之间的光谱差异可追溯到与脓毒症发病率相关的细菌菌株的特异性糖结合物。这项工作说明了在临床烧伤创面护理中将 EVs 作为生物标记物的潜在应用价值,并证明拉曼分析是一种快速、无标记的方法,可在宿主背景中特异性地识别与感染相关的细菌 EVs 特征。
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Journal of Extracellular Vesicles
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