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Extracellular vesicles miR-31-5p promotes pancreatic cancer chemoresistance via regulating LATS2-Hippo pathway and promoting SPARC secretion from pancreatic stellate cells 细胞外囊泡miR-31-5p通过调节LATS2-Hippo通路和促进胰腺星状细胞分泌SPARC促进胰腺癌化疗抗性
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1002/jev2.12488
Cheng Qin, Bangbo Zhao, Yuanyang Wang, Zeru Li, Tianyu Li, Yutong Zhao, Weibin Wang, Yupei Zhao

Pancreatic cancer remains one of the most lethal malignant diseases. Gemcitabine-based chemotherapy is still one of the first-line systemic treatments, but chemoresistance occurs in the majority of patients. Recently, accumulated evidence has demonstrated the role of the tumour microenvironment in promoting chemoresistance. In the tumour microenvironment, pancreatic stellate cells (PSCs) are among the main cellular components, and extracellular vesicles (EVs) are common mediators of cell‒cell communication. In this study, we showed that SP1-transcribed miR-31-5p not only targeted LATS2 in pancreatic cancer cells but also regulated the Hippo pathway in PSCs through EV transfer. Consequently, PSCs synthesized and secreted protein acidic and rich in cysteins (SPARC), which was preferentially expressed in stromal cells, stimulating Extracellular Signal regulated kinase (ERK) signalling in pancreatic cancer cells. Therefore, pancreatic cancer cell survival and chemoresistance were improved due to both the intrinsic Hippo pathway regulated by miR-31-5p and external SPARC-induced ERK signalling. In mouse models, miR-31-5p overexpression in pancreatic cancer cells promoted the chemoresistance of coinjected xenografts. In a tissue microarray, pancreatic cancer patients with higher miR-31-5p expression had shorter overall survival. Therefore, miR-31-5p regulates the Hippo pathway in multiple cell types within the tumour microenvironment via EVs, ultimately contributing to the chemoresistance of pancreatic cancer cells.

胰腺癌仍然是最致命的恶性疾病之一。以吉西他滨为基础的化疗仍是一线系统治疗方法之一,但大多数患者会出现化疗耐药性。近来,不断积累的证据证明了肿瘤微环境在促进化疗耐药方面的作用。在肿瘤微环境中,胰腺星状细胞(PSCs)是主要的细胞成分之一,而细胞外囊泡(EVs)是细胞与细胞间通讯的常见介质。本研究表明,SP1转录的miR-31-5p不仅能靶向胰腺癌细胞中的LATS2,还能通过EV转移调控PSCs中的Hippo通路。因此,胰腺干细胞合成并分泌了酸性富含半胱氨酸的蛋白质(SPARC),这种蛋白质优先在基质细胞中表达,从而刺激了胰腺癌细胞的细胞外信号调节激酶(ERK)信号传导。因此,miR-31-5p调控的内在Hippo通路和SPARC诱导的外部ERK信号都能改善胰腺癌细胞的生存和化疗耐受性。在小鼠模型中,miR-31-5p 在胰腺癌细胞中的过表达促进了共注射异种移植的化疗抗性。在组织芯片中,miR-31-5p 表达较高的胰腺癌患者总生存期较短。因此,miR-31-5p通过EVs调节肿瘤微环境中多种细胞类型的Hippo通路,最终导致胰腺癌细胞的化疗抗性。
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引用次数: 0
A Predictive Model for Initial Platinum-Based Chemotherapy Efficacy in Patients with Postoperative Epithelial Ovarian Cancer Using Tissue-Derived Small Extracellular Vesicles 利用组织来源的细胞外小泡建立卵巢上皮癌术后患者初始铂类化疗疗效预测模型
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1002/jev2.12486
Shizhen Shen, Conghui Wang, Jiaxin Gu, Feifei Song, Xiaodong Wu, Fangfang Qian, Xiaojing Chen, Lingfang Wang, Qiaohua Peng, Ziyu Xing, Lingkai Gu, Fenfen Wang, Xiaodong Cheng

Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.

上皮性卵巢癌(EOC)是一种经常致命的恶性肿瘤,其特点是对铂类化疗产生耐药性。因此,准确预测铂类药物的疗效对于战略性地选择术后干预措施以降低与次优治疗效果和不良反应相关的风险至关重要。组织来源的细胞外囊泡(tsEVs)与血浆来源的细胞外囊泡不同,是研究 EOC 组织独特属性的有力工具。在这项研究中,对从58名铂敏感和30名铂耐药的EOC患者体内获得的tsEV进行了4D数据独立采集(DIA)蛋白质组测序。分析结果表明,差异表达的蛋白质明显富集,这些蛋白质主要与免疫相关通路有关。此外,还通过 LASSO 回归确定了关键的免疫相关蛋白(IRPs)。这些因素与通过单变量逻辑回归筛选出的临床参数相结合,用于构建多变量逻辑回归模型。该模型将三个 tsEV IRPs(CCR1、IGHV_35 和 CD72)与一个临床参数(是否存在术后残留病灶)整合在一起。因此,该模型可以预测EOC患者术后初始铂类化疗的疗效,甚至在开始化疗之前就能提供预后信息。
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引用次数: 0
Expression of the αVβ3 integrin affects prostate cancer sEV cargo and density and promotes sEV pro-tumorigenic activity in vivo through a GPI-anchored receptor, NgR2 αVβ3整合素的表达会影响前列腺癌sEV的载货量和密度,并通过GPI锚定受体NgR2促进体内sEV的促肿瘤活性。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-06 DOI: 10.1002/jev2.12482
Cecilia E. Verrillo, Fabio Quaglia, Christopher D. Shields, Stephen Lin, Andrew V. Kossenkov, Hsin-Yao Tang, David Speicher, Nicole M. Naranjo, Anna Testa, William K. Kelly, Qin Liu, Benjamin Leiby, Luca Musante, Khalid Sossey-Alaoui, Navneet Dogra, Tzu-Yi Chen, Dario C. Altieri, Lucia R. Languino

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.

众所周知,小细胞外囊泡(sEVs)从癌细胞中释放出来,并通过与受体细胞的串联促进癌症的发展。我们以前曾报道过,表达αVβ3整合素(一种在侵袭性神经内分泌前列腺癌(NEPrCa)中上调的蛋白质)的sEVs有助于受体细胞的神经内分泌分化(NED)。本研究采用碘克沙醇密度梯度分离 sEV,并通过纳米颗粒追踪分析、免疫印迹和单囊分析对其进行表征。与对照组相比,我们对含有αVβ3的sEVs进行的蛋白质组学分析表明,参与细胞凋亡和坏死的典型效应因子下调,而肿瘤细胞存活因子上调。我们还发现,在 sEVs 中表达 αVβ3 会导致 EV 标记(Alix、CD81、CD9)明显重新定位到低密度 sEV 亚群。这种低密度重新定位与细胞外基质(ECM)蛋白与 sEV 的相互作用无关。这种 sEV 亚群包含 αVβ3 和 αVβ3 下游效应物 NgR2,NgR2 是 NEPrCa 的新型标记物。我们发现,与不表达αVβ3的sEV相比,含有αVβ3的sEV负载了更多的NgR2。从机理上讲,我们证明了含有 NgR2 的 sEVs 不会影响 sEV 的标记特征,但当它们在体内肿瘤内注射时,会促进肿瘤生长并诱导 NED。我们的研究表明,表达 NgR2 的 sEV 会增加受体细胞中焦点粘附激酶(FAK)的活化,FAK 是一种已知的癌细胞增殖促进因子。我们还表明,NgR2 可模拟含有 αVβ3 的 sEVs 的效应,因为与对照细胞相比,NgR2 转染细胞在体内的生长速度加快。总之,我们的研究结果描述了含有αVβ3整合素及其效应物NgR2的癌细胞衍生sEV在货物、密度和功能方面发生的变化,而不影响sEV的四聚体概况。
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引用次数: 0
Mesenchymal stromal/stem cell tissue source and in vitro expansion impact extracellular vesicle protein and miRNA compositions as well as angiogenic and immunomodulatory capacities 间充质基质/干细胞组织来源和体外扩增会影响细胞外囊泡蛋白和 miRNA 成分以及血管生成和免疫调节能力。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-02 DOI: 10.1002/jev2.12472
Yuan Liu, Li Sun, Yan Li, Christina Holmes

Recently, therapies utilizing extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) have begun to show promise in clinical trials. However, EV therapeutic potential varies with MSC tissue source and in vitro expansion through passaging. To find the optimal MSC source for clinically translatable EV-derived therapies, this study aims to compare the angiogenic and immunomodulatory potentials and the protein and miRNA cargo compositions of EVs isolated from the two most common clinical sources of adult MSCs, bone marrow and adipose tissue, across different passage numbers. Primary bone marrow-derived MSCs (BMSCs) and adipose-derived MSCs (ASCs) were isolated from adult female Lewis rats and expanded in vitro to the indicated passage numbers (P2, P4, and P8). EVs were isolated from the culture medium of P2, P4, and P8 BMSCs and ASCs and characterized for EV size, number, surface markers, protein content, and morphology. EVs isolated from different tissue sources showed different EV yields per cell, EV sizes, and protein yield per EV. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of proteomics data and miRNA seq data identified key proteins and pathways associated with differences between BMSC-EVs and ASC-EVs, as well as differences due to passage number. In vitro tube formation assays employing human umbilical vein endothelial cells suggested that both tissue source and passage number had significant effects on the angiogenic capacity of EVs. With or without lipopolysaccharide (LPS) stimulation, EVs more significantly impacted expression of M2-macrophage genes (IL-10, Arg1, TGFβ) than M1-macrophage genes (IL-6, NOS2, TNFα). By correlating the proteomics analyses with the miRNA seq analysis and differences observed in our in vitro immunomodulatory, angiogenic, and proliferation assays, this study highlights the trade-offs that may be necessary in selecting the optimal MSC source for development of clinical EV therapies.

最近,利用间充质基质/干细胞(MSCs)产生的细胞外囊泡(EVs)进行治疗的方法开始在临床试验中显示出前景。然而,EV 的治疗潜力因间叶干细胞组织来源和体外扩增传代而异。为了找到可转化为临床EV衍生疗法的最佳间充质干细胞来源,本研究旨在比较从临床上最常见的两种成人间充质干细胞来源(骨髓和脂肪组织)分离出来的EV在不同通过数下的血管生成和免疫调节潜能以及蛋白质和miRNA载体组成。从成年雌性 Lewis 大鼠体内分离出原发性骨髓间充质干细胞(BMSCs)和脂肪间充质干细胞(ASCs),并在体外扩增至指定的培养倍数(P2、P4 和 P8)。从 P2、P4 和 P8 BMSCs 和 ASCs 的培养液中分离出 EVs,并对 EVs 的大小、数量、表面标记、蛋白质含量和形态进行表征。从不同组织来源分离的EV显示出不同的单位细胞EV产量、EV大小和单位EV蛋白产量。通过对蛋白质组学数据和 miRNA seq 数据进行基因本体论(GO)和京都基因组百科全书(KEGG)通路分析,确定了与 BMSC-EVs 和 ASC-EVs 之间的差异有关的关键蛋白质和通路,以及因通过数而产生的差异。利用人体脐静脉内皮细胞进行的体外血管形成试验表明,组织来源和通过数对EVs的血管生成能力都有显著影响。无论是否有脂多糖(LPS)刺激,EVs 对 M2-巨噬细胞基因(IL-10、Arg1、TGFβ)表达的影响比 M1-巨噬细胞基因(IL-6、NOS2、TNFα)更明显。通过将蛋白质组学分析与 miRNA 序列分析以及在体外免疫调节、血管生成和增殖试验中观察到的差异联系起来,本研究强调了在为开发临床 EV 疗法选择最佳间充质干细胞来源时可能需要进行的权衡。
{"title":"Mesenchymal stromal/stem cell tissue source and in vitro expansion impact extracellular vesicle protein and miRNA compositions as well as angiogenic and immunomodulatory capacities","authors":"Yuan Liu,&nbsp;Li Sun,&nbsp;Yan Li,&nbsp;Christina Holmes","doi":"10.1002/jev2.12472","DOIUrl":"10.1002/jev2.12472","url":null,"abstract":"<p>Recently, therapies utilizing extracellular vesicles (EVs) derived from mesenchymal stromal/stem cells (MSCs) have begun to show promise in clinical trials. However, EV therapeutic potential varies with MSC tissue source and in vitro expansion through passaging. To find the optimal MSC source for clinically translatable EV-derived therapies, this study aims to compare the angiogenic and immunomodulatory potentials and the protein and miRNA cargo compositions of EVs isolated from the two most common clinical sources of adult MSCs, bone marrow and adipose tissue, across different passage numbers. Primary bone marrow-derived MSCs (BMSCs) and adipose-derived MSCs (ASCs) were isolated from adult female Lewis rats and expanded in vitro to the indicated passage numbers (P2, P4, and P8). EVs were isolated from the culture medium of P2, P4, and P8 BMSCs and ASCs and characterized for EV size, number, surface markers, protein content, and morphology. EVs isolated from different tissue sources showed different EV yields per cell, EV sizes, and protein yield per EV. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of proteomics data and miRNA seq data identified key proteins and pathways associated with differences between BMSC-EVs and ASC-EVs, as well as differences due to passage number. In vitro tube formation assays employing human umbilical vein endothelial cells suggested that both tissue source and passage number had significant effects on the angiogenic capacity of EVs. With or without lipopolysaccharide (LPS) stimulation, EVs more significantly impacted expression of M2-macrophage genes (IL-10, Arg1, TGFβ) than M1-macrophage genes (IL-6, NOS2, TNFα). By correlating the proteomics analyses with the miRNA seq analysis and differences observed in our in vitro immunomodulatory, angiogenic, and proliferation assays, this study highlights the trade-offs that may be necessary in selecting the optimal MSC source for development of clinical EV therapies.</p>","PeriodicalId":15811,"journal":{"name":"Journal of Extracellular Vesicles","volume":null,"pages":null},"PeriodicalIF":15.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875019","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
Normothermic liver perfusion derived extracellular vesicles have concentration-dependent immunoregulatory properties 常温肝脏灌注衍生的细胞外囊泡具有浓度依赖性免疫调节特性。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12485
Heather Jennings, Stacey McMorrow, Peter Chlebeck, Grace Heise, Mia Levitsky, Bret Verhoven, John A. Kink, Kristin Weinstein, Seungpyo Hong, David P. Al-Adra

Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross-decoration’. In contrast, donor liver-derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant-relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti-inflammatory miRNA species. In terms of function, liver-derived EVs were able to cross-decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration-dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF-α, IL-10 and IFN-γ. In conclusion, we determined physiologically produced liver-derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.

细胞外囊泡(EVs)是实体器官移植后免疫反应的主要因素。供体衍生的EVs最著名的作用是通过将供体主要组织相容性复合体蛋白转移到受体抗原呈递细胞而导致移植排斥反应,这种现象被称为 "交叉修饰"。与此相反,在小动物模型中,供体肝脏来源的EV与器官耐受有关。因此,EVs 及其载体的细胞来源可能会影响其下游免疫效应。为了研究肝脏在生理学和移植相关模型中释放的EVs的免疫效应,我们分离了在常温体外肝脏灌注(NEVLP)过程中产生的EVs,这是一种在移植前储存肝脏的新方法。我们发现肝脏在NEVLP过程中产生了EVs,这些EVs含有多种抗炎miRNA。在功能方面,肝脏衍生的EVs能够交叉修饰异体细胞,并以浓度依赖的方式抑制异体混合淋巴细胞反应中的免疫反应。就细胞因子反应而言,在混合淋巴细胞反应中加入 1 × 109 EVs 能显著减少炎性细胞因子 TNF-α、IL-10 和 IFN-γ 的产生。总之,我们确定了生理产生的肝源性 EVs 具有免疫调节作用,这对它们在实体器官移植中的作用和可能的改变具有影响。
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引用次数: 0
Baohuoside I chemosensitises breast cancer to paclitaxel by suppressing extracellular vesicle/CXCL1 signal released from apoptotic cells 宝藿苷 I 通过抑制凋亡细胞释放的细胞外囊泡/CXCL1 信号,使乳腺癌对紫杉醇产生化疗敏感性。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12493
Shengqi Wang, Jing Li, Shang Xu, Neng Wang, Bo Pan, Bowen Yang, Yifeng Zheng, Juping Zhang, Fu Peng, Cheng Peng, Zhiyu Wang

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

三阴性乳腺癌(TNBC)是侵袭性最强的乳腺癌亚型,化疗是治疗 TNBC 的基础疗法。令人遗憾的是,新的研究结果表明,化疗促进了肿瘤微环境的转移变化。细胞外囊泡(EVs)与癌症的耐药性和转移密切相关。然而,从濒死癌细胞中释放的EVs对TNBC预后的影响以及相应的治疗策略还鲜有研究。本研究表明,紫杉醇化疗可诱导凋亡的TNBC细胞产生富含CXCL1的EVs(EV-Apo)。EV-Apo通过激活PD-L1信号,使M2巨噬细胞极化,从而促进了共培养TNBC细胞的化疗耐药性和侵袭。然而,宝藿苷I(BHS)通过调节EV-Apo信号传导,显著提高了共培养TNBC细胞对紫杉醇化疗的敏感性。从机理上讲,BHS 显著减少了 EV-Apo 中的 C-X-C motif 趋化因子配体 1(CXCL1)载体,从而通过抑制 PD-L1 的活化减轻了巨噬细胞的 M2 极化。此外,BHS还通过减少TNBC细胞多泡体(MVB)内腔内囊泡(ILV)的生物生成来减少EV-Apo的释放。此外,BHS还能与flotillin 2(FLOT2)的LEU104残基结合,中断其与RAS癌基因家族成员31(RAB31)的相互作用,从而阻断RAB31-FLOT2复合物驱动的ILV生物生成。重要的是,BHS通过抑制EV-ApoCXCL1诱导的PD-L1活化和肿瘤相关巨噬细胞(TAMs)的M2极化,显著提高了紫杉醇的化疗敏感性,从而抑制了TNBC在体内的转移。这项开创性的研究揭示了EV-ApoCXCL1作为一种新型治疗靶点对TNBC化疗的敏感性,并将BHS作为一种有前景的化疗辅助剂,通过干扰EV-ApoCXCL1的生物生成来改善TNBC的化疗敏感性和预后。
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引用次数: 0
Extracellular vesicle surface display of αPD-L1 and αCD3 antibodies via engineered late domain-based scaffold to activate T-cell anti-tumor immunity 通过基于晚期结构域的工程支架在细胞外囊泡表面展示 αPD-L1 和 αCD3 抗体,以激活 T 细胞抗肿瘤免疫。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12490
Rui Chen, Ziqin Kang, Wenhao Li, Tianshu Xu, Yongqiang Wang, Qiming Jiang, Yuepeng Wang, Zixian Huang, Xiaoding Xu, Zhiquan Huang

Extracellular vesicles (EVs) are emerging as promising carriers for the delivery of therapeutic biologics. Genetic engineering represents a robust strategy for loading proteins of interest into EVs. Identification of EV-enriched proteins facilitates protein cargo loading efficiency. Many EV-enriched proteins are sorted into EVs via an endosomal sorting complex required for transport (ESCRT)-dependent pathway. In parallel, viruses hijack this EV biosynthesis machinery via conserved late domain motifs to promote egress from host cells. Inspired by the similarity of biogenesis between EVs and viruses, we developed a synthetic, Late domain-based EV scaffold protein that enables the display of a set of single chain variable fragments (scFvs) on the EV surface. We named this scaffold the Late domain-based exosomal antibody surface display platform (LEAP). We applied the LEAP scaffold to reprogramme HEK293T cell-derived EVs to elicit T-cell anti-tumor immunity by simultaneously displaying αPD-L1 and αCD3 scFvs on the EV surface (denoted as αPD-L1×αCD3 bispecific T-cell engaging exosomes, BiTExos). We demonstrated that αPD-L1×αCD3 BiTExos actively redirected T cells to bind to PD-L1+ tumor cells, promoting T-cell activation, proliferation and tumoricidal cytokine production. Furthermore, the αPD-L1×αCD3 BiTExos promoted T-cell infiltration into the tumor microenvironment to mitigate the tumor burden in vivo. Our study suggested that the LEAP scaffold may serve as a platform for EV surface display and could be applied for a broad range of EV-based biomedical applications.

细胞外囊泡(EVs)正在成为输送治疗性生物制剂的理想载体。基因工程是将感兴趣的蛋白质装载到 EVs 中的有力策略。鉴定 EV 富集蛋白有助于提高蛋白质货物的装载效率。许多EV富集蛋白都是通过一种依赖于内体运输所需的分选复合物(ESCRT)的途径分选到EV中的。与此同时,病毒通过保守的晚期结构域基团劫持这一EV生物合成机制,以促进从宿主细胞中排出。受EV和病毒之间相似的生物发生机制的启发,我们开发了一种基于晚期结构域的合成EV支架蛋白,它能在EV表面显示一组单链可变片段(scFvs)。我们将这种支架命名为基于晚期结构域的外泌体抗体表面展示平台(LEAP)。我们应用 LEAP 支架对 HEK293T 细胞衍生的外泌体进行了重编程,通过在外泌体表面同时展示 αPD-L1 和 αCD3 scFvs 来诱导 T 细胞抗肿瘤免疫(称为 αPD-L1×αCD3 双特异性 T 细胞吸引外泌体,BiTExos)。我们证实,αPD-L1×αCD3 BiTExos能主动引导T细胞与PD-L1+肿瘤细胞结合,促进T细胞活化、增殖和杀伤肿瘤细胞因子的产生。此外,αPD-L1×αCD3 BiTExos 还能促进 T 细胞浸润肿瘤微环境,减轻体内肿瘤负荷。我们的研究表明,LEAP支架可作为一种EV表面展示平台,并可广泛应用于基于EV的生物医学领域。
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引用次数: 0
Human placental mesenchymal stromal cell-derived small extracellular vesicles as a treatment for severe COVID-19: A double-blind randomized controlled clinical trial 用人胎盘间充质基质细胞衍生的小细胞外囊泡治疗严重的 COVID-19:双盲随机对照临床试验。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12492
Mohammad Hossein Zamanian, Amir Hossein Norooznezhad, Zohreh Hosseinkhani, Daryoush Hassaninia, Feizollah Mansouri, Siavash Vaziri, Mehrdad Payandeh, Fatemeh Heydarpour, Sara Kiani, Maria Shirvani, Mojgan Rajati, Mitra Bakhtiari, Farzaneh Esmaili, Reza Yarani, Kamran Mansouri

The current study aimed to investigate the effects of human placental mesenchymal stromal cell-derived small extracellular vesicles (hPMSC-sEVs) as a treatment for COVID-19. This double-blind, randomized, controlled clinical trial was conducted on two groups of patients with COVID-19-associated acute respiratory distress syndrome. After randomization, the control group received standard treatment and placebo, and the intervention arm received standard treatment plus hPMSC-sEVs. The number of hospital deaths was considered the primary outcome. After meeting the exclusion and inclusion criteria, 21 and 24 patients were allocated to intervention and control arms, respectively. Besides admission SpO2 levels, which were significantly lower in the intervention arm (p = 0.008), all the baseline demo-biographic and laboratory variables were similar between the groups. It was shown that hPMSC-sEVs could significantly (p = 0.015) decrease the mortality ratio in the intervention group (4/21 [19.04%]) compared to the controls (13/24 [54.16%]). The mean time to death in the intervention and control groups was 28.06 and 11.10 days, respectively (p < 0.001). This study showed that hPMSC-sEVs are a possible treatment for critically ill patients with COVID-19.

本研究旨在探讨人胎盘间充质基质细胞衍生的小细胞外囊泡(hPMSC-sEVs)治疗 COVID-19 的效果。这项双盲、随机对照临床试验针对两组 COVID-19 相关急性呼吸窘迫综合征患者进行。随机分组后,对照组接受标准治疗和安慰剂,干预组接受标准治疗和 hPMSC-sEVs。住院死亡人数被视为主要结果。符合排除和纳入标准后,21 名和 24 名患者分别被分配到干预组和对照组。除了入院时的 SpO2 水平在干预组明显降低(p = 0.008)外,两组患者的所有基线人口学和实验室变量均相似。结果显示,与对照组(13/24 [54.16%])相比,干预组(4/21 [19.04%])的死亡率明显降低(p = 0.015)。干预组和对照组的平均死亡时间分别为 28.06 天和 11.10 天(p = 0.015)。
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引用次数: 0
Cell dehydration enables massive production of engineered membrane vesicles with therapeutic functions 细胞脱水可大量生产具有治疗功能的工程膜囊泡。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12483
Jie Liu, Tingting Shen, Yu Zhang, Xiaojian Wei, Yuting Bao, Rui Ai, Shaoju Gan, Dachi Wang, Xin Lai, Libo Zhao, Wei Zhou, Xiaohong Fang

Extracellular vesicles (EVs) have emerged as promising biomaterials for the treatment of different disease. However, only handful types of EVs with clinical transformation potential have been reported to date, and their preparation on a large scale under biosafety-controlled conditions is limited. In this study, we characterize a novel type of EV with promising clinical application potential: dehydration-induced extracellular vesicles (DIMVs). DIMV is a type of micron-diameter cell vesicle that contains more bioactive molecules, such as proteins and RNA, but not DNA, than previously reported cell vesicles. The preparation of DIMV is extraordinarily straightforward, which possesses a high level of biosafety, and the protein utilization ratio is roughly 600 times greater than that of naturally secreted EVs. Additional experiments demonstrate the viability of pre- or post-isolation DIMV modification, including gene editing, nucleic acid encapsulation or surface anchoring, size adjustment. Finally, on animal models, we directly show the biosafety and immunogenicity of DIMV, and investigate its potential application as tumour vaccine or drug carrier in cancer treatment.

细胞外囊泡(EVs)已成为治疗不同疾病的有前途的生物材料。然而,迄今为止,具有临床转化潜能的EVs只有少数几种,而且在生物安全可控条件下大规模制备EVs的技术也很有限。在这项研究中,我们描述了一种具有临床应用潜力的新型EV:脱水诱导细胞外囊泡(DIMVs)。DIMV 是一种微米直径的细胞外囊泡,与之前报道的细胞外囊泡相比,它含有更多的生物活性分子,如蛋白质和 RNA,但不包括 DNA。DIMV 的制备非常简单,具有很高的生物安全性,其蛋白质利用率大约是自然分泌型 EV 的 600 倍。其他实验证明了分离前或分离后对 DIMV 进行修饰的可行性,包括基因编辑、核酸封装或表面锚定、大小调整等。最后,我们在动物模型上直接展示了 DIMV 的生物安全性和免疫原性,并研究了其作为肿瘤疫苗或药物载体在癌症治疗中的潜在应用。
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引用次数: 0
RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release RAB22A 将上皮细胞生长因子受体(EGFR)从早期内体运送到循环内体,以释放微囊。
IF 15.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1002/jev2.12494
Yujie Lin, Denghui Wei, Xiaobo He, Lanqing Huo, Jingxuan Wang, Xia Zhang, Yuanzhong Wu, Ruhua Zhang, Ying Gao, Tiebang Kang

Microvesicles (MVs) containing proteins, nucleic acid or organelles are shed from the plasma membrane. Although the mechanisms of MV budding are well elucidated, the connection between endosomal trafficking and MV formation remains poorly understood. In this report, RAB22A is revealed to be crucial for EGFR-containing MVs formation by the RAB GTPase family screening. RAB22A recruits TBC1D2B, a GTPase-activating protein (GAP) of RAB7A, to inactivate RAB7A, thus preventing EGFR from being transported to late endosomes and lysosomes. RAB22A also engages SH3BP5L, a guanine-nucleotide exchange factor (GEF) of RAB11A, to activate RAB11A on early endosomes. Consequently, EGFR is recycled to the cell surface and packaged into MVs. Furthermore, EGFR can phosphorylate RAB22A at Tyr136, which in turn promotes EGFR-containing MVs formation. Our findings illustrate that RAB22A acts as a sorter on early endosomes to sort EGFR to recycling endosomes for MV shedding by both activating RAB11A and inactivating RAB7A.

含有蛋白质、核酸或细胞器的微囊泡(MV)从质膜上脱落。尽管微囊泡出芽的机制已被很好地阐明,但人们对内质体转运与微囊泡形成之间的联系仍然知之甚少。在本报告中,通过对 RAB GTPase 家族的筛选,发现 RAB22A 对含表皮生长因子受体的 MV 的形成至关重要。RAB22A 招募 RAB7A 的 GTP 酶激活蛋白(GAP)TBC1D2B,使 RAB7A 失活,从而阻止表皮生长因子受体被转运到晚期内体和溶酶体。RAB22A 还与 RAB11A 的鸟嘌呤核苷酸交换因子(GEF)SH3BP5L 结合,激活早期内体上的 RAB11A。因此,表皮生长因子受体被回收到细胞表面,并被包装成膜质。此外,表皮生长因子受体还能使 RAB22A 在 Tyr136 处磷酸化,进而促进含表皮生长因子受体的 MV 的形成。我们的研究结果表明,RAB22A 可作为早期内体的分拣器,通过激活 RAB11A 和使 RAB7A 失活,将表皮生长因子受体分拣到循环内体以脱落 MV。
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引用次数: 0
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Journal of Extracellular Vesicles
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