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Amniotic fluid stem cell-derived extracellular vesicles educate type 2 conventional dendritic cells to rescue autoimmune disorders in a multiple sclerosis mouse model 羊水干细胞衍生的细胞外囊泡教育2型常规树突状细胞,挽救多发性硬化症小鼠模型的自身免疫紊乱。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-06-06 DOI: 10.1002/jev2.12446
Giorgia Manni, Marco Gargaro, Doriana Ricciuti, Simona Fontana, Eleonora Padiglioni, Marco Cipolloni, Tommaso Mazza, Jessica Rosati, Alessandra di Veroli, Giulia Mencarelli, Benedetta Pieroni, Estevão Carlos Silva Barcelos, Giulia Scalisi, Francesco Sarnari, Alessandro di Michele, Luisa Pascucci, Francesca de Franco, Teresa Zelante, Cinzia Antognelli, Gabriele Cruciani, Vincenzo Nicola Talesa, Rita Romani, Francesca Fallarino

Dendritic cells (DCs) are essential orchestrators of immune responses and represent potential targets for immunomodulation in autoimmune diseases. Human amniotic fluid secretome is abundant in immunoregulatory factors, with extracellular vesicles (EVs) being a significant component. However, the impact of these EVs on dendritic cells subsets remain unexplored. In this study, we investigated the interaction between highly purified dendritic cell subsets and EVs derived from amniotic fluid stem cell lines (HAFSC-EVs). Our results suggest that HAFSC-EVs are preferentially taken up by conventional dendritic cell type 2 (cDC2) through CD29 receptor-mediated internalization, resulting in a tolerogenic DC phenotype characterized by reduced expression and production of pro-inflammatory mediators. Furthermore, treatment of cDC2 cells with HAFSC-EVs in coculture systems resulted in a higher proportion of T cells expressing the regulatory T cell marker Foxp3 compared to vehicle-treated control cells. Moreover, transfer of HAFSC-EV-treated cDC2s into an EAE mouse model resulted in the suppression of autoimmune responses and clinical improvement. These results suggest that HAFSC-EVs may serve as a promising tool for reprogramming inflammatory cDC2s towards a tolerogenic phenotype and for controlling autoimmune responses in the central nervous system, representing a potential platform for the study of the effects of EVs in DC subsets.

树突状细胞(DC)是免疫反应的重要协调者,也是自身免疫性疾病免疫调节的潜在靶点。人类羊水分泌物组富含免疫调节因子,其中细胞外囊泡 (EV) 是重要的组成部分。然而,这些EVs对树突状细胞亚群的影响仍有待探索。在这项研究中,我们调查了高度纯化的树突状细胞亚群与羊水干细胞系衍生的EVs(HAFSC-EVs)之间的相互作用。我们的研究结果表明,HAFSC-EVs 通过 CD29 受体介导的内化作用,优先被传统的 2 型树突状细胞(cDC2)吸收,从而形成一种以减少表达和产生促炎介质为特征的耐受性 DC 表型。此外,在共培养系统中用HAFSC-EV处理cDC2细胞后,表达调节性T细胞标记物Foxp3的T细胞比例高于用药物处理的对照细胞。此外,将经 HAFSC-EV 处理的 cDC2 移植到 EAE 小鼠模型中,可抑制自身免疫反应并改善临床症状。这些结果表明,HAFSC-EV 可以作为一种很有前途的工具,将炎症性 cDC2 重编程为耐受表型,并控制中枢神经系统的自身免疫反应,是研究 EV 在 DC 亚群中的作用的潜在平台。
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引用次数: 0
Milk-derived extracellular vesicles functionalized with anti-tumour necrosis factor-α nanobody and anti-microbial peptide alleviate ulcerative colitis in mice 用抗肿瘤坏死因子-α纳米抗体和抗微生物肽功能化的牛奶衍生细胞外囊泡可缓解小鼠的溃疡性结肠炎。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-06-05 DOI: 10.1002/jev2.12462
Renwei Jing, Leijie Zhang, Ruibin Li, Zhongqiu Yang, Jun Song, Qian Wang, Nan Cao, Gang Han, HaiFang Yin

Ulcerative colitis (UC) manifests clinically with chronic intestinal inflammation and microflora dysbiosis. Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk-derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell-penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti-tumour necrosis factor-α (TNF-α) nanobody (VHHm3F) (EVVHH) via TAT significantly reduced tissue TNF-α levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EVLV), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC-induced depression and anxiety. Collectively, we demonstrated that oral delivery of EVLV effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug-loaded orally-administrable EV treatment for other diseases.

溃疡性结肠炎(UC)的临床表现为慢性肠道炎症和微生态失调。虽然生物制剂可以有效控制炎症,但要将其高效地输送到结肠和结肠上皮细胞仍具有挑战性。牛奶衍生的细胞外囊泡(EV)有望成为一种口服给药工具,然而,将生物制剂装入EV的能力给治疗应用带来了挑战。在这里,我们证明了将细胞穿透肽(TAT)与绿色荧光蛋白(GFP)融合可将生物制剂装载到EV中,并在体外和体内口服给药后防止其在胃肠道环境中降解。与单独使用VHH相比,通过TAT口服载入抗肿瘤坏死因子-α(TNF-α)纳米抗体(VHHm3F)(EVVHH)的EV能显著降低急性UC小鼠组织中的TNF-α水平,减轻病理变化。在慢性 UC 小鼠中,将 VHH 和抗菌肽 LL37 同时导入 EV(EVLV),然后口服,可改善肠道屏障、炎症和微生物群平衡,缓解 UC 引起的抑郁和焦虑。总之,我们证明了口服 EVLV 能有效缓解小鼠的 UC,而 TAT 能有效地将生物制剂载入 EV,使其免受胃肠道降解的影响。这种治疗策略对治疗多发性硬化症很有希望,而且是一种简单、可推广的方法,可用于其他疾病的药物口服EV治疗。
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引用次数: 0
Taenia solium cysticerci's extracellular vesicles Attenuate the AKT/mTORC1 pathway for Alleviating DSS-induced colitis in a murine model 恙虫胞外囊泡可减轻 AKT/mTORC1 通路,从而缓解小鼠模型中由 DSS 引起的结肠炎。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-23 DOI: 10.1002/jev2.12448
Suraj Singh Rawat, Anand Kumar Keshri, Naina Arora, Rimanpreet Kaur, Amit Mishra, Rajiv Kumar, Amit Prasad

The excretory–secretory proteome plays a pivotal role in both intercellular communication during disease progression and immune escape mechanisms of various pathogens including cestode parasites like Taenia solium. The cysticerci of T. solium causes infection in the central nervous system known as neurocysticercosis (NCC), which affects a significant population in developing countries. Extracellular vesicles (EVs) are 30–150-nm-sized particles and constitute a significant part of the secretome. However, the role of EV in NCC pathogenesis remains undetermined. Here, for the first time, we report that EV from T. solium larvae is abundant in metabolites that can negatively regulate PI3K/AKT pathway, efficiently internalized by macrophages to induce AKT and mTOR degradation through auto-lysosomal route with a prominent increase in the ubiquitination of both proteins. This results in less ROS production and diminished bacterial killing capability among EV-treated macrophages. Due to this, both macro-autophagy and caspase-linked apoptosis are upregulated, with a reduction of the autophagy substrate sequestome 1. In summary, we report that T. solium EV from viable cysts attenuates the AKT–mTOR pathway thereby promoting apoptosis in macrophages, and this may exert immunosuppression during an early viable stage of the parasite in NCC, which is primarily asymptomatic. Further investigation on EV-mediated immune suppression revealed that the EV can protect the mice from DSS-induced colitis and improve colon architecture. These findings shed light on the previously unknown role of T. solium EV and the therapeutic role of their immune suppression potential.

排泄-分泌蛋白质组在疾病进展过程中的细胞间通信和各种病原体的免疫逃逸机制中都发挥着关键作用,其中包括像蛔虫这样的绦虫寄生虫。蛔虫的囊尾蚴会导致中枢神经系统感染,被称为神经囊尾蚴病(NCC),影响着发展中国家的大量人口。细胞外囊泡(EVs)是 30-150 纳米大小的颗粒,是分泌物的重要组成部分。然而,EV在NCC发病机制中的作用仍未确定。在这里,我们首次报道了蜱幼虫的EV富含能负向调节PI3K/AKT通路的代谢物,能被巨噬细胞有效内化,通过自身溶酶体途径诱导AKT和mTOR降解,同时这两种蛋白的泛素化显著增加。这导致经 EV 处理的巨噬细胞产生的 ROS 减少,杀死细菌的能力减弱。因此,巨噬细胞自噬和与 Caspase 链接的细胞凋亡都被上调,自噬底物 sequestome 1 减少。总之,我们报告说,来自存活囊肿的梭形芽孢杆菌 EV 可减弱 AKT-mTOR 通路,从而促进巨噬细胞的凋亡,这可能会在寄生虫在 NCC 中的早期存活阶段(主要是无症状阶段)发挥免疫抑制作用。对 EV 介导的免疫抑制的进一步研究发现,EV 可以保护小鼠免受 DSS 诱导的结肠炎的影响,并改善结肠结构。这些发现揭示了蜱EV之前未知的作用及其免疫抑制潜力的治疗作用。
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引用次数: 0
Correction to “Exhaled breath condensate contains extracellular vesicles (EVs) that carry miRNA cargos of lung tissue origin that can be selectively purified and analyzed” 更正为 "呼出的气体冷凝物中含有细胞外囊泡 (EV),这些囊泡携带肺组织来源的 miRNA 货物,可选择性地对其进行纯化和分析"。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-21 DOI: 10.1002/jev2.12453

Megan I. Mitchell, Iddo Z. Ben-Dov, Kenny Ye, Christina Liu, Miao Shi, Ali Sadoughi, Chirag Shah, Taha Siddiqui, Aham Okorozo, Martin Gutierrez, Rashmi Unawane, Lisa Biamonte, Kaushal Parikh, Simon Spivack, Olivier Loudig

In the originally published article, author Kaushal Parikh's name was misspelled. This has been corrected in the online version of the article.

We apologize for this error.

Megan I. Mitchell, Iddo Z. Ben-Dov, Kenny Ye, Christina Liu, Miao Shi, Ali Sadoughi, Chirag Shah, Taha Siddiqui, Aham Okorozo, Martin Gutierrez, Rashmi Unawane, Lisa Biamonte, Kaushal Parikh, Simon Spivack, Olivier Loudig在最初发表的文章中,作者Kaushal Parikh的名字拼错了。我们对此错误深表歉意。
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引用次数: 0
Lipid A in outer membrane vesicles shields bacteria from polymyxins 外膜囊泡中的脂质 A 使细菌免受多粘菌素的侵害。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-20 DOI: 10.1002/jev2.12447
Marie Burt, Georgia Angelidou, Christopher Nils Mais, Christian Preußer, Timo Glatter, Thomas Heimerl, Rüdiger Groß, Javier Serrania, Gowtham Boosarpu, Elke Pogge von Strandmann, Janis A. Müller, Gert Bange, Anke Becker, Mareike Lehmann, Danny Jonigk, Lavinia Neubert, Hinrich Freitag, Nicole Paczia, Bernd Schmeck, Anna Lena Jung

The continuous emergence of multidrug-resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae being a prominent threat. We conducted a comprehensive study on K. pneumoniae’s antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last-resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)-stressed K. pneumoniae exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Klebsiella. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In all models, OMVs protected K. pneumoniae from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed K. pneumoniae could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed K. pneumoniae compared to control OMVs. The lipid A-dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Klebsiella from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross-protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug-resistant bacterial infections.

耐多药细菌病原体的不断出现对全球医疗保健构成了重大挑战,其中肺炎克雷伯氏菌是一个突出的威胁。我们对肺炎克雷伯菌的抗生素耐药机制进行了全面研究,重点是外膜囊泡和多粘菌素(一种最后的抗生素)。我们的研究表明,外膜囊泡能保护细菌免受多粘菌素的侵害。与未受多粘菌素影响的克雷伯氏菌的外膜囊泡相比,受多粘菌素 B(PB)影响的肺炎克雷伯氏菌的外膜囊泡由于囊泡化增加而显示出更强的保护效力。OMV 还能保护不同细菌科的细菌。我们使用精密切片肺片(PCLS)和鼠伤寒杆菌对这一点进行了体内外验证。在所有模型中,OMV 都能保护肺炎双球菌免受 PB 感染,并降低蛋白质水平上的相关应激反应。我们观察到 OMVs 的脂质组成在 PB 处理后发生了重大变化,从而影响了它们与 PB 的结合能力。肺炎克雷伯菌受到 PB 胁迫后,其单个 OMVs 的结合能力发生了改变,这可能与其释放的囊泡中的脂质 A 数量减少有关。虽然每个囊泡的脂质 A 量减少了,但由于脂质 A 的总和增加了,因此 PB 结合位点也增加了,囊泡数量的总体增加导致了保护能力的增强。这就揭示了与对照 OMV 相比,肺炎克氏菌受 PB 胁迫的 OMV 对 PB 的保护效力发生改变的机制。利用人工囊泡在体外证实了脂质 A 依赖性对 PB 的保护作用。此外,人工囊泡在体内外都成功地保护了克雷伯氏菌免受肺炎双球菌的感染。研究结果表明,OMV 可通过与多粘菌素结合,有效地充当诱饵,阻止抗生素与细胞表面的相互作用,从而起到保护细菌的作用。我们的研究结果为了解抗生素交叉保护的机制提供了宝贵的见解,并为开发新型治疗干预措施提供了潜在的途径,以应对不断升级的耐多药细菌感染的威胁。
{"title":"Lipid A in outer membrane vesicles shields bacteria from polymyxins","authors":"Marie Burt,&nbsp;Georgia Angelidou,&nbsp;Christopher Nils Mais,&nbsp;Christian Preußer,&nbsp;Timo Glatter,&nbsp;Thomas Heimerl,&nbsp;Rüdiger Groß,&nbsp;Javier Serrania,&nbsp;Gowtham Boosarpu,&nbsp;Elke Pogge von Strandmann,&nbsp;Janis A. Müller,&nbsp;Gert Bange,&nbsp;Anke Becker,&nbsp;Mareike Lehmann,&nbsp;Danny Jonigk,&nbsp;Lavinia Neubert,&nbsp;Hinrich Freitag,&nbsp;Nicole Paczia,&nbsp;Bernd Schmeck,&nbsp;Anna Lena Jung","doi":"10.1002/jev2.12447","DOIUrl":"10.1002/jev2.12447","url":null,"abstract":"<p>The continuous emergence of multidrug-resistant bacterial pathogens poses a major global healthcare challenge, with <i>Klebsiella pneumoniae</i> being a prominent threat. We conducted a comprehensive study on <i>K. pneumoniae</i>’s antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last-resort antibiotic. Our research demonstrates that OMVs protect bacteria from polymyxins. OMVs derived from Polymyxin B (PB)-stressed <i>K. pneumoniae</i> exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed <i>Klebsiella</i>. OMVs also shield bacteria from different bacterial families. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and <i>Galleria mellonella</i>. In all models, OMVs protected <i>K. pneumoniae</i> from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. The altered binding capacity of single OMVs from PB stressed <i>K. pneumoniae</i> could be linked to a reduction in the lipid A amount of their released vesicles. Although the amount of lipid A per vesicle is reduced, the overall increase in the number of vesicles results in an increased protection because the sum of lipid A and therefore PB binding sites have increased. This unravels the mechanism of the altered PB protective efficacy of OMVs from PB stressed <i>K. pneumoniae</i> compared to control OMVs. The lipid A-dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected <i>Klebsiella</i> from PB ex vivo and in vivo. The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross-protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug-resistant bacterial infections.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":null,"pages":null},"PeriodicalIF":16.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jev2.12447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065752","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
Correction to “Cell-engineered virus-mimetic nanovesicles for vaccination against enveloped viruses” 对 "用于包膜病毒疫苗接种的细胞工程病毒仿生纳米颗粒 "的更正。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-17 DOI: 10.1002/jev2.12452

Han, C., Kim, S., Seo, Y., Lim, M., Kwon, Y., Yi, J., Oh, S.-I., Kang, M., Jeon, S. G., & Park, J. (2024). Cell-engineered virus-mimetic nanovesicles for vaccination against enveloped viruses. Journal of Extracellular Vesicles, 13, e12438. https://doi.org/10.1002/jev2.12438

In the originally published article, the acknowledgements section was incorrect. The correct text is as follows:

Han, C., Kim, S., Seo, Y., Lim, M., Kwon, Y., Yi, J., Oh, S.-I., Kang, M., Jeon, S. G., & Park, J. (2024)。用于包膜病毒疫苗接种的细胞工程病毒仿生纳米囊泡。Journal of Extracellular Vesicles, 13, e12438. https://doi.org/10.1002/jev2.12438In 最初发表的文章中,致谢部分有误。正确内容如下
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引用次数: 0
A novel multi-stage enrichment workflow and comprehensive characterization for HEK293F-derived extracellular vesicles 新型多级富集工作流程和 HEK293F 衍生细胞外囊泡的综合表征。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-17 DOI: 10.1002/jev2.12454
Nhan Vo, Chau Tran, Nam H. B. Tran, Nhat T. Nguyen, Thieu Nguyen, Duyen T. K. Ho, Diem D. N. Nguyen, Tran Pham, Tien Anh Nguyen, Hoa T. N. Phan, Hoai-Nghia Nguyen, Lan N. Tu

Extracellular vesicles (EVs) are emerging as a promising drug delivery vehicle as they are biocompatible and capable of targeted delivery. However, clinical translation of EVs remains challenging due to the lack of standardized and scalable manufacturing protocols to consistently isolate small EVs (sEVs) with both high yield and high purity. The heterogenous nature of sEVs leading to unknown composition of biocargos causes further pushback due to safety concerns. In order to address these issues, we developed a robust quality-controlled multi-stage process to produce and isolate sEVs from human embryonic kidney HEK293F cells. We then compared different 2-step and 3-step workflows for eliminating protein impurities and cell-free nucleic acids to meet acceptable limits of regulatory authorities. Our results showed that sEV production was maximized when HEK293F cells were grown at high-density stationary phase in semi-continuous culture. The novel 3-step workflow combining tangential flow filtration, sucrose-cushion ultracentrifugation and bind-elute size-exclusion chromatography outperformed other methods in sEV purity while still preserved high yield and particle integrity. The purified HEK293F-derived sEVs were thoroughly characterized for identity including sub-population analysis, content profiling including proteomics and miRNA sequencing, and demonstrated excellent preclinical safety profile in both in-vitro and in-vivo testing. Our rigorous enrichment workflow and comprehensive characterization will help advance the development of EVs, particularly HEK293F-derived sEVs, to be safe and reliable drug carriers for therapeutic applications.

细胞外囊泡(EVs)具有良好的生物相容性和靶向给药能力,正在成为一种前景广阔的给药载体。然而,由于缺乏标准化和可扩展的生产规程来持续分离出高产率和高纯度的小EVs(sEVs),EVs的临床转化仍面临挑战。sEVs 的异质性导致生物卡戈的成分不明,从而引发了更多的安全问题。为了解决这些问题,我们开发了一种稳健的多阶段质量控制流程,用于从人类胚胎肾脏 HEK293F 细胞中生产和分离 sEV。然后,我们比较了消除蛋白质杂质和无细胞核酸的不同 2 步和 3 步工作流程,以满足监管机构的可接受限值。我们的结果表明,当 HEK293F 细胞在半连续培养的高密度静止期生长时,sEV 的产量最大。新颖的三步工作流程结合了切向流过滤、蔗糖垫超速离心法和碱性排阻色谱法,在保持高产率和颗粒完整性的同时,在 sEV 纯度方面优于其他方法。我们对纯化的 HEK293F 衍生 sEV 进行了全面的特性鉴定,包括亚群分析、蛋白质组学和 miRNA 测序等内容分析,并在体外和体内测试中证明了其出色的临床前安全性。我们严格的富集工作流程和全面的特征描述将有助于推动 EVs(尤其是 HEK293F 衍生的 sEVs)的发展,使其成为安全可靠的药物载体,用于治疗应用。
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引用次数: 0
Extracellular vesicles as human therapeutics: A scoping review of the literature 作为人类疗法的细胞外囊泡:文献综述。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-13 DOI: 10.1002/jev2.12433
Clorinda Fusco, Giusy De Rosa, Ilaria Spatocco, Elisabetta Vitiello, Claudio Procaccini, Chiara Frigè, Valeria Pellegrini, Rosalba La Grotta, Roberto Furlan, Giuseppe Matarese, Francesco Prattichizzo, Paola de Candia

Extracellular vesicles (EVs) are released by all cells and contribute to cell-to-cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans.

The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well-designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options.

细胞外囊泡 (EV) 由所有细胞释放,有助于细胞间的交流。由于细胞外囊泡具有靶向特定细胞和高效传递功能分子复合特征的能力,世界各地的研究人员都在假设它们作为治疗药物的潜力。尽管在动物模型中对 EV 治疗进行了大量研究,但其对人类的实际临床益处却迟迟未得到验证。在这次范围界定综述中,我们检索了 PubMed 和其他数据库(截至 2023 年 12 月 31 日),从 13,567 条记录中选出了 40 项相关的已发表研究,测试 EVs 作为人类疗法的效果。对这 40 项研究的分析表明,它们都是小型试验,在给药途径和目标疾病方面存在很大的异质性。此外,大多数研究都没有安慰剂对照,EV制剂主要用于局部,给药剂量指标也不一致,这些都妨碍了对不同研究进行比较,也无法就EV的安全性和有效性得出确切结论。另一方面,一些有希望的结果也强烈呼吁进行精心设计的更大规模研究,以测试 EV 作为治疗人类疾病的替代方法,而目前还没有或只有很少的治疗选择。
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引用次数: 0
Correction to “Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches” 更正 "细胞外囊泡研究的最基本信息(MISEV2023):从基本方法到高级方法"。
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-10 DOI: 10.1002/jev2.12451

Welsh, J. A., Goberdhan, D. C. I., O'Driscoll, L., Buzas, E. I., Blenkiron, C., Bussolati, B., Cai, H., Di Vizio, D., Driedonks, T. A. P., Erdbrügger, U., Falcon-Perez, J. M., Fu, Q.-L., Hill, A. F., Lenassi, M., Lim, S. K., Mahoney, M. G., Mohanty, S., Möller, A., Nieuwland, R., … Witwer, K. W. (2024). Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. Journal of Extracellular Vesicles, 13, e12404. https://doi.org/10.1002/jev2.12404

In the originally published article, Gisela D'Angelo was omitted from the MISEV Consortium. They have been added to the online version of the article. We apologize for this error.

Welsh, J. A., Goberdhan, D. C. I., O'Driscoll, L., Buzas, E. I., Blenkiron, C., Bussolati, B., Cai, H., Di Vizio, D., Driedonks, T. A. P., Erdbrügger, U.、Falcon-Perez, J. M., Fu, Q.-L., Hill, A. F., Lenassi, M., Lim, S. K., Mahoney, M. G., Mohanty, S., Möller, A., Nieuwland, R., ... Witwer, K. W. (2024).细胞外囊泡研究的最基本信息(MISEV2023):从基本方法到高级方法。Journal of Extracellular Vesicles, 13, e12404. https://doi.org/10.1002/jev2.12404In 在最初发表的文章中,Gisela D'Angelo 被 MISEV Consortium 略去。他们已被添加到文章的在线版本中。我们对此错误深表歉意。
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引用次数: 0
Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells 对用于心脏修复的细胞外小泡的相关细胞来源进行正面比较:胚胎干细胞的优越性
IF 16 1区 医学 Q1 Medicine Pub Date : 2024-05-06 DOI: 10.1002/jev2.12445
Hernán González-King, Patricia G. Rodrigues, Tamsin Albery, Benyapa Tangruksa, Ramya Gurrapu, Andreia M. Silva, Gentian Musa, Dominika Kardasz, Kai Liu, Bengt Kull, Karin Åvall, Katarina Rydén-Markinhuhta, Tania Incitti, Nitin Sharma, Cecilia Graneli, Hadi Valadi, Kasparas Petkevicius, Miguel Carracedo, Sandra Tejedor, Alena Ivanova, Sepideh Heydarkhan-Hagvall, Phillipe Menasché, Jane Synnergren, Niek Dekker, Qing-Dong Wang, Karin Jennbacken

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI.

在心肌梗塞(MI)的临床前模型中,来自不同细胞来源的小细胞外囊泡(sEV)已被证明能增强心脏功能。本研究的目的是比较不同来源的 sEV 对心脏修复的作用,并确定最有效的 sEV。我们在体外心脏修复模型中全面评估了从人类原代骨髓间充质基质细胞(BM-MSC)、人类永生化间充质干细胞(hTERT-MSC)、人类胚胎干细胞(ESC)、ESC衍生的心脏祖细胞(CPC)、人类ESC衍生的心肌细胞(CM)和人类原代心室成纤维细胞(VCF)中获得的sEV的功效。ESC衍生的sEV(ESC-sEV)在体外表现出最佳的促血管生成和抗纤维化效果。然后,我们在小鼠心肌缺血再灌注损伤(IRI)模型中评估了体外表现最出色的 sEV 的功能,并分析了它们的 RNA 和蛋白质组成。在体内,ESC-sEV 通过下调纤维化和增加血管生成来减少不良的心脏重塑,从而在心肌梗死后提供最有利的结果。此外,从 hTERT-MSC、ESC 和 CPC 中提取的 sEV 的转录组和蛋白质组特征揭示了 ESC-sEV 中可能驱动所观察到的功能的因素。总之,ESC-sEV 作为一种无细胞疗法,在促进心肌梗死后的心脏修复方面大有可为。
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Journal of Extracellular Vesicles
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