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Small extracellular vesicles derived from human induced pluripotent stem cell-differentiated neural progenitor cells mitigate retinal ganglion cell degeneration in a mouse model of optic nerve injury
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作者 Tong Li Hui-Min Xing +4 位作者 Hai-Dong Qian Qiao Gao Sheng-Lan Xu Hua Ma Zai-Long Chi 《Neural Regeneration Research》 SCIE CAS 2025年第2期587-597,共11页
Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limit... Several studies have found that transplantation of neural progenitor cells(NPCs)promotes the survival of injured neurons.However,a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application.Small extracellular vesicles(sEVs)contain bioactive molecules for neuronal protection and regeneration.Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases.In this study,we intravitreally transplanted sEVs derived from human induced pluripotent stem cells(hiPSCs)and hiPSCs-differentiated NPCs(hiPSC-NPC)in a mouse model of optic nerve crush.Our results show that these intravitreally injected sEVs were ingested by retinal cells,especially those localized in the ganglion cell layer.Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration,and regulated the retinal microenvironment by inhibiting excessive activation of microglia.Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells,which had protective effects on RGCs after optic nerve injury.These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy. 展开更多
关键词 EXOSOME miRNA neural progenitor cell NEURODEGENERATION NEUROINFLAMMATION neuroprotection optic nerve crush optic neuropathy retinal ganglion cell small extracellular vesicles
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Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery
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作者 Yi Zhang Zhongwu Liu +7 位作者 Michael Chopp Michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang 《Neural Regeneration Research》 SCIE CAS 2025年第1期224-233,共10页
Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso... Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling. 展开更多
关键词 axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke
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Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization
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作者 Zeyan Liang Zhelun Yang +5 位作者 Haishu Xie Jian Rao Xiongjie Xu Yike Lin Chunhua Wang Chunmei Chen 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第10期2259-2269,共11页
Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)... Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury. 展开更多
关键词 bone marrow mesenchymal stem cells hypoxia preconditioning interleukin-1 receptor-associated kinase 1 MACROPHAGES mesenchymal stem cells small extracellular vesicles spinal cord injury
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Small Extracellular Vesicles Secreted by Peri-urethral Tissues Regulate Fibroblast Function and Contribute to the Pathogenesis of Female Stress Urinary Incontinence 被引量:1
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作者 Ning CHEN Xiao-yan SUN +4 位作者 Zhi-chen DING Jia-qi HU Wen-juan LI Li ZHAN Zhen-wei XIE 《Current Medical Science》 SCIE CAS 2023年第4期803-810,共8页
Objective:This study aimed to explore the existence of small extracellular vesicles(sEVs)in peri-urethral tissues and the role of abnormal expression of sEVs in the pathogenesis of female stress urinary incontinence(S... Objective:This study aimed to explore the existence of small extracellular vesicles(sEVs)in peri-urethral tissues and the role of abnormal expression of sEVs in the pathogenesis of female stress urinary incontinence(SUI).Methods:sEVs were extracted from peri-urethral vaginal wall tissues using differential centrifugation and were observed by transmission electron microscopy(TEM).The number of sEVs and their protein contents were compared between SUI and control groups using nanoparticle tracking analysis(NTA)and bicinchoninic acid(BCA)protein assay.Fibroblasts were cultured separately with SUI(SsEVs group)and normal tissue sEVs(NsEVs group).Proliferation and migration of fibroblasts were compared between groups using CCK-8 and wound healing assays,respectively.Expression levels of collagenⅠandⅢwere compared among blank control(BC),NsEVs,and SsEVs groups using real-time PCR.Protein mass spectrometry was used to test the differentially expressed proteins contained in sEVs between groups.Results:sEVs were extracted and found under the electron microscope.There were significantly more sEVs extracted from the SUI group compared to the normal group.Fibroblasts showed increased proliferative and decreased migratory abilities,and expressed more collagen in the SsEVs group compared to the NsEVs and BC groups.Protein spectrum analysis demonstrated several differentially expressed targets,including components of microfibrils,elastin polymer,and anti-inflammatory factors.Conclusion:sEVs were detected in the peri-urethral tissues.SUI tissues expressed more sEVs than control.The abnormal expression of sEVs and their protein contents may contribute to the pathogenesis and progression of SUI. 展开更多
关键词 collagen female stress urinary incontinence FIBROBLASTS small extracellular vesicles
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Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes 被引量:4
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作者 Hai-Li Lang Yan-Zhi Zhao +4 位作者 Ren-Jie Xiao Jing Sun Yong Chen Guo-Wen Hu Guo-Hai Xu 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第3期609-617,共9页
Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,ho... Postoperative cognitive dysfunction(POCD)is a common surgical complication.Diabetes mellitus(DM)increases risk of developing POCD after surgery.DM patients with POCD seriously threaten the quality of patients’life,however,the intrinsic mechanism is unclear,and the effective treatment is deficiency.Previous studies have demonstrated neuronal loss and reduced neurogenesis in the hippocampus in mouse models of POCD.In this study,we constructed a mouse model of DM by intraperitoneal injection of streptozotocin,and then induced postoperative cognitive dysfunction by transient bilateral common carotid artery occlusion.We found that mouse models of DM-POCD exhibited the most serious cognitive impairment,as well as the most hippocampal neural stem cells(H-NSCs)loss and neurogenesis decline.Subsequently,we hypothesized that small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells(iMSC-sEVs)might promote neurogenesis and restore cognitive function in patients with DM-POCD.iMSC-sEVs were administered via the tail vein beginning on day 2 after surgery,and then once every 3 days for 1 month thereafter.Our results showed that iMSC-sEVs treatment significantly recovered compromised proliferation and neuronal-differentiation capacity in H-NSCs,and reversed cognitive impairment in mouse models of DM-POCD.Furthermore,miRNA sequencing and qPCR showed miR-21-5p and miR-486-5p were the highest expression in iMSC-sEVs.We found iMSC-sEVs mainly transferred miR-21-5p and miR-486-5p to promote H-NSCs proliferation and neurogenesis.As miR-21-5p was demonstrated to directly targete Epha4 and CDKN2C,while miR-486-5p can inhibit FoxO1 in NSCs.We then demonstrated iMSC-sEVs can transfer miR-21-5p and miR-486-5p to inhibit EphA4,CDKN2C,and FoxO1 expression in H-NSCs.Collectively,these results indicate significant H-NSC loss and neurogenesis reduction lead to DM-POCD,the application of iMSC-sEVs may represent a novel cell-free therapeutic tool for diabetic patients with postoperative cognitive dysfunction. 展开更多
关键词 diabetes mellitus hippocampus induced pluripotent stem cell mesenchymal stem cell miRNA neural stem cell NEUROGENESIS postoperative cognitive dysfunction signaling pathway small extracellular vesicle
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Mesenchymal stem cell-derived small extracellular vesicles in the treatment of human diseases:Progress and prospect 被引量:10
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作者 Jie Shi Yu-Chen Zhao +5 位作者 Zhi-Fang Niu Hao-Jun Fan Shi-Ke Hou Xiao-Qin Guo Lu Sang Qi Lv 《World Journal of Stem Cells》 SCIE 2021年第1期49-63,共15页
Mesenchymal stem cells(MSCs)are self-renewing,multipotent cells that could differentiate into multiple tissues.MSC-based therapy has become an attractive and promising strategy for treating human diseases through immu... Mesenchymal stem cells(MSCs)are self-renewing,multipotent cells that could differentiate into multiple tissues.MSC-based therapy has become an attractive and promising strategy for treating human diseases through immune regulation and tissue repair.However,accumulating data have indicated that MSC-based therapeutic effects are mainly attributed to the properties of the MSC-sourced secretome,especially small extracellular vesicles(sEVs).sEVs are signaling vehicles in intercellular communication in normal or pathological conditions.sEVs contain natural contents,such as proteins,mRNA,and microRNAs,and transfer these functional contents to adjacent cells or distant cells through the circulatory system.MSC-sEVs have drawn much attention as attractive agents for treating multiple diseases.The properties of MSC-sEVs include stability in circulation,good biocompatibility,and low toxicity and immunogenicity.Moreover,emerging evidence has shown that MSC-sEVs have equal or even better treatment efficacies than MSCs in many kinds of disease.This review summarizes the current research efforts on the use of MSC-sEVs in the treatment of human diseases and the existing challenges in their application from lab to clinical practice that need to be considered. 展开更多
关键词 Mesenchymal stem cells small extracellular vesicles EXOSOMES Human diseases THERAPEUTICS PROSPECTS
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Small extracellular vesicles encapsulating lefty1 mRNA inhibit hepatic fibrosis
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作者 Yarong Zhao Yang Yu +2 位作者 Simiao Wang Jiaxin Li Lesheng Teng 《Asian Journal of Pharmaceutical Sciences》 SCIE CAS 2022年第5期630-640,共11页
Liver fibrosis is the deposition of extracellular matrix(ECM)in the liver caused by persistent chronic injury,which can lead to more serious diseases such as cirrhosis or cancer.Blocking the effect of transforming gro... Liver fibrosis is the deposition of extracellular matrix(ECM)in the liver caused by persistent chronic injury,which can lead to more serious diseases such as cirrhosis or cancer.Blocking the effect of transforming growth factorβ1(TGF-β1),one of the most important cytokines in liver fibrosis,may be one of the effective ways to inhibit liver fibrosis.As a kind of natural nano-scale vesicles,small extracellular vesicles(sEvs)have displayed excellent delivery vehicle properties.Herein,we prepared hepatic stellate cell(HSC)-derived sEvs loading left-right determination factor 1(lefty1)mRNA(sEvLs)and we wanted to verify whether they can inhibit fibrosis by blocking the TGF-β1 signaling pathway.The results showed that sEvLs had effective cell uptake and reduced activation of HSCs.Rats that were injected with CCl 4 by intraperitoneal injection for 6 weeks exhibited obvious symptoms of liver fibrosis and were treated with systemically administered sEvLs and free sEvs for 4 weeks.Rats injected with olive oil alone served as sham controls.Administration of sEvLs significantly reduced the area of fibrosis compared with free sEvs.We demonstrated that sEvLs inhibited HSCs activation and ECM production,and promote ECM degradation by downregulatingα-smooth muscle actin(α-SMA),collagen I,tissue inhibitor of metalloproteinase(TIMP)-1 and upregulating matrix metalloprotease(MMP)-1.In summary,as an endogenous delivery vehicle,sEvs could deliver mRNA to attenuate hepatic fibrosis by blocking the TGF-β/Smad signaling pathway. 展开更多
关键词 Liver fibrosis Hepatic stellate cells small extracellular vesicles Transforming growth factorβ1 Lefty1
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A review from mesenchymal stem-cells and their small extracellular vesicles in tissue engineering
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作者 ODIN RAMIREZ-FERNANDEZ ESMERALDA ZUÑIGA-AGUILAR 《BIOCELL》 SCIE 2022年第2期325-338,共14页
This review aims to offer a vision of the clinical reality of cell therapy today in intensive medicine.For this,it has been carried out a description of the properties,functions,and Mesenchymal Stem Cells(MSCS)sources... This review aims to offer a vision of the clinical reality of cell therapy today in intensive medicine.For this,it has been carried out a description of the properties,functions,and Mesenchymal Stem Cells(MSCS)sources to subsequently address the evidence in preclinical models and studies clinical trials with whole cells and models attributed to small extracellular vesicles(sEVs),nanoparticles made up of microvesicles secreted by cells with an effect on the extracellular matrix,and their impact as an alternative towards cell-free regenerative medicine.MSCs are cells that enhance the regenerative capacity which can be differentiated typically in different lineages committed as bone,cartilage,and adipose tissue.On the other hand,small extracellular vesicles are structures that participate notoriously and crucially in intercellular communication,which has led to a change in the concept of the functions and the role that these vesicles play in living organisms,in the restoration of damaged tissues and the inflammatory response and immunological.We present the mechanisms that are involved in the applications of MSCS as whole cells and their sEVs in cell therapy and cell-free therapy as an alternative in regenerative medicine.Considering the structural loss that occurs after surgical procedures for cystic and tumoral pathology in periodontitis,as well as the maxillary atrophy that determines the rehabilitation with dental implants,it is imperative to find satisfactory solutions.The opportunity provided by the findings in stem cells is a recent introduction in the field of oral surgery,based on the regenerative potential that these cells possess to restore defects at different levels of the oral cavity.This review aims to discover the real applications that stem cells may have in our treatments shortly. 展开更多
关键词 Tissue engineering Mesenchymal stem cells small extracellular vesicles Acute graft-versus-host disease Cell culture Cell differentiation
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Small extracellular vesicles and liver diseases:From diagnosis to therapy
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作者 Atsunori Tsuchiya Kazuki Natsui +6 位作者 Yui Ishii Yohei Koseki Nobutaka Takeda Kei Tomiyoshi Fusako Yamazaki Yuki Yoshida Shuji Terai 《World Journal of Hepatology》 2022年第7期1307-1318,共12页
Extracellular vesicles(EVs),especially small EVs(sEVs)derived from liver cells,have been the focus of much attention in the normal physiology and pathogenesis of various diseases affecting the liver.sEVs are approxima... Extracellular vesicles(EVs),especially small EVs(sEVs)derived from liver cells,have been the focus of much attention in the normal physiology and pathogenesis of various diseases affecting the liver.sEVs are approximately 100 nm in size,enclosed within lipid bilayers,and are very stable.The lipids,proteins,and nucleic acids,including miRNAs,contained within these vesicles are known to play important roles in intercellular communication.This mini-review summarizes the application of sEVs.First,liver diseases and the related diagnostic markers are described,and the current active status of miRNA research in diagnosis of hepatocellular carcinoma(HCC)is reported.Second,the biodistribution and pharmacokinetics of sEVs are described,and the liver is highlighted as the organ with the highest accumulation of sEVs.Third,the relationship between sEVs and the pathogenesis of liver disorders is described with emphesis on the current active status of miRNA research in HCC recurrence and survival.Finally,the possibility of future therapy using sEVs from mesenchymal stem(stromal)cells for cirrhosis and other diseases is described. 展开更多
关键词 small extracellular vesicles LIVER CIRRHOSIS Hepatocellular carcinoma Mesenchymal stem cells
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NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma
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作者 Yue Yao Yi Xu +7 位作者 Liang Yu Ting-Mao Xue Zhi-Jie Xiao Pui-Chi Tin Hiu-Ling Fung Hoi-Tang Ma Jing-Ping Yun Judy Wai Ping Yam 《Cancer Communications》 SCIE 2024年第2期251-272,共22页
Background:Small extracellular vesicles(sEVs)mediate intercellular commu-nication that contributes to hepatocellular carcinoma(HCC)progression via multifaceted pathways.The success of cell entry determines the effect ... Background:Small extracellular vesicles(sEVs)mediate intercellular commu-nication that contributes to hepatocellular carcinoma(HCC)progression via multifaceted pathways.The success of cell entry determines the effect of sEV on recipient cells.Here,we aimed to delineate the mechanisms underlying the uptake of sEV in HCC.Abbreviations:AF,Alexa Fluor;ANOVA,analysis of variance;ATP9A,ATPase Phospholipid Transporting 9A;BCECF-AM,2’,7’-bis-(2-barboxyethyl)-5-(and-6)-carboxyfluorescein,acetoxymethyl ester;BSA,bovine serum albumin;CCMR,Centre for Comparative Medicine Research;CRISPR,clustered regularly interspaced short palindromic repeats;CTL,ctrl;CXCR4,C-X-C Chemokine Receptor Type 4;DAPI,4′,6-diamidino-2-phenylindole;DFS,disease-free survival;DMEM,Dulbecco’s Modified Eagle Medium;DMSO,dimethyl sulfoxide;Dox,doxycycline;EEA1,early endosome antigen 1;EIPA,5-(N-ethyl-N-isopropyl)-amiloride;FBS,fetal bovine serum;FITC,fluorescein isothiocyanate;GAPDH,glyceraldehyde-3-phosphate dehydrogenase;GM130,Golgi matrix protein 130;HCC,hepatocellular carcinoma;HEPES,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;HPRT1,hypoxanthine phosphoribosyltransferase 1;H-score,histoscore;IAA,indole-3-acetic acid;KD,knockdown;KO,knockout;mAID,mini-auxin-inducible degron;MTT,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;NHE7,Na(+)/H(+)exchanger 7;ns,non-significant;OD,optical density;OS,overall survival;PBS,phosphate-buffered saline;PCR,polymerase chain reaction;pHe,endosomal pH;pHi,intracellular pH;PKH67,Paul Karl Horan 67;Rab21,Ras-associated binding protein 21;RIPA,radioimmunoprecipitation assay;SAM,synergistic activation mediator;SEMs,standard error of the means;sEVs,small extracellular vesicles;sgRNA,single-guide RNA;shRNA,short-hairpin RNA;SLC9,solute carrier gene 9;SLiCE,Seamless Ligation Cloning Extract;TCGA,The Cancer Genome Atlas;TCL,total cell lysates;TGN,trans-Golgi network;TMA,tissue microarray;TMR,tetramethyl rhodamine;TSG101,tumor susceptibility gene 101.Yue Yao and Yi Xu contributed equally to this work.Methods:Macropinocytosis was examined by the ability of cells to internalize dextran and sEV.Macropinocytosis was analyzed in Na(+)/H(+)exchanger 7(NHE7)-knockdown and-overexpressing cells.The properties of cells were stud-ied using functional assays.pH biosensor was used to evaluate the intracellular and endosomal pH.The expression of NHE7 in patients’liver tissues was exam-ined by immunofluorescent staining.Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7.Results:The data revealed that macropinocytosis controlled the internaliza-tion of sEVs and their oncogenic effect on recipient cells.It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non-metastatic HCC cells.Attenuation of macropinocytic activity by 5-(N-ethyl-N-isopropyl)-amiloride(EIPA)limited the entry of sEVs and compromised cell aggressiveness.Mechanistically,we delineated that high level of NHE7,a sodium-hydrogen exchanger,alkalized intracellular pH and acidized endosomal pH,leading to the maturation of macropinosomes.Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis.Clinically,NHE7 expression was upregulated and linked to dismal prognosis of HCC.Conclusions:This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells.Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC. 展开更多
关键词 hepatocellular carcinoma small extracellular vesicles MACROPINOCYTOSIS pH regulation sodium-hydrogen exchanger
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MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression
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作者 Yanjin WANG Yifei CHEN +5 位作者 Fuji YANG Xiaolong YU Ying CHU Jing ZHOU Yongmin YAN Jianbo XI 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2024年第7期594-604,共11页
Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like prote... Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis.Mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver disorders.Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues.It is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC activation.Additionally,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis.This study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis development.The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC.Moreover,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro.MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model.MSC-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 cells.In conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases. 展开更多
关键词 Mesenchymal stem cell(MSC) small extracellular vesicle(sEV) MicroRNA-4465(miR-4465) Hepatic stellate cell(HSC) Liver fibrosis
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Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles 被引量:4
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作者 Ziqiang Chu Qilin Huang +12 位作者 Kui Ma Xi Liu Wenhua Zhang Shengnan Cui Qian Wei Huanhuan Gao Wenzhi Hu Zihao Wang Sheng Meng Lige Tian Haihong Li Xiaobing Fu Cuiping Zhang 《Bioactive Materials》 SCIE CSCD 2023年第9期257-270,共14页
Neutrophil extracellular traps(NETs)have been considered a significant unfavorable factor for wound healing in diabetes,but the mechanisms remain unclear.The therapeutic application of small extracellular vesicles(sEV... Neutrophil extracellular traps(NETs)have been considered a significant unfavorable factor for wound healing in diabetes,but the mechanisms remain unclear.The therapeutic application of small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)has received considerable attention for their properties.Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine.Therefore,the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs(Hypo-sEVs).Excessive NETs were found in diabetic wounds and in high glucose(HG)-induced neutrophils.Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum(ER)stress.Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p.Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway.Additionally,miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts,similar to the effects of Hypo-sEVs.Overall,we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment. 展开更多
关键词 Diabetic wound healing Neutrophil extracellular traps small extracellular vesicles HYPOXIA Endoplasmic reticulum stress
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Small extracellular vesicles derived from hypoxic preconditioned dental pulp stem cells ameliorate inflammatory osteolysis by modulating macrophage polarization and osteoclastogenesis 被引量:4
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作者 Jun Tian Weiyang Chen +8 位作者 Yuhua Xiong Qianer Li Siyi Kong Mengjie Li Chunfeng Pang Yu Qiu Zhezhen Xu Qimei Gong Xi Wei 《Bioactive Materials》 SCIE CSCD 2023年第4期326-342,共17页
Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown ... Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown to exert therapeutic effects on bone defects.However,cultured MSCs are typically exposed to normoxia(21%O2)in vitro,which differs largely from the oxygen concentration in vivo under hypoxic conditions.It is largely unknown whether sEV derived from dental pulp stem cells(DPSCs)cultured under hypoxic conditions(Hypo-sEV)exert better therapeutic effects on lipopolysaccharide(LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions(Nor-sEV)by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis.In this study,we show that hypoxia significantly induces the release of sEV from DPSCs.Moreover,Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV.Mechanistically,hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV.MiR-210-3p is enriched in Hypo-sEV,and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105,which attenuates osteolysis.Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression. 展开更多
关键词 Dental pulp stem cells small extracellular vesicles Macrophage OSTEOCLAST Inflammatory osteolysis
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Role of Small Extracellular Vesicles in Liver Diseases:Pathogenesis,Diagnosis,and Treatment 被引量:5
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作者 Tingmao Xue Judy Wai Ping Yam 《Journal of Clinical and Translational Hepatology》 SCIE 2022年第6期1176-1185,共10页
Extracellular vesicles(EVs)are vesicular bodies that bud off from the cell membrane or are secreted virtually by all cell types.Small EVs(sEVs or exosomes)are key mediators of cell-cell communication by delivering the... Extracellular vesicles(EVs)are vesicular bodies that bud off from the cell membrane or are secreted virtually by all cell types.Small EVs(sEVs or exosomes)are key mediators of cell-cell communication by delivering their cargo,including proteins,lipids,or RNAs,to the recipient cells where they induce changes in signaling pathways and phenotypic prop-erties.Tangible findings have revealed the pivotal involve-ment of sEVs in the pathogenesis of various diseases.On the bright side,they are rich sources of biomarkers for diag-nosis,prognosis,treatment response,and disease monitor-ing.sEVs have high stability,biocompatibility,targetability,low toxicity,and are immunogenic in nature.Their intrinsic properties make sEVs an ideal delivery vehicle to be loaded with cargo for therapeutic interventions.Liver diseases are a major global health problem.This review aims to focus on the roles and mechanisms of sEVs in the pathogenesis of liver diseases,liver injury,liver failure,and liver can-cer.sEVs are released not only by hepatocytes but also by stromal and immune cells in the microenvironment.Early detection of liver disease determines the chance for cura-tive treatment and high survival of patients.This review focuses on the potential of circulating sEV cargo as specific and sensitive noninvasive biomarkers for the early detection and prognosis of liver diseases.In addition,the therapeutic use of sEVs derived from various cell types is discussed.Al-though sEVs hold promise for clinical applications,there are still challenges to be overcome by further research to bring utilization of sEVs into clinical practice. 展开更多
关键词 small extracellular vesicles Liver injury Liver fibrosis Liver fail-ure Hepatocellular carcinoma Biomarkers.
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Small extracellular vesicles with nanomorphology memory promote osteogenesis 被引量:3
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作者 Liang Ma Wencan Ke +11 位作者 Zhiwei Liao Xiaobo Feng Jie Lei Kun Wang Bingjin Wang Gaocai Li Rongjin Luo Yunsong Shi Weifeng Zhang Yu Song Weibin Sheng Cao Yang 《Bioactive Materials》 SCIE 2022年第11期425-438,共14页
Nanotopographical cues endow biomaterials the ability to guide cell adhesion, proliferation, and differentiation. Cellular mechanical memory can maintain the cell status by retaining cellular information obtained from... Nanotopographical cues endow biomaterials the ability to guide cell adhesion, proliferation, and differentiation. Cellular mechanical memory can maintain the cell status by retaining cellular information obtained from past mechanical microenvironments. Here, we propose a new concept “morphology memory of small extracellular vesicles (sEV)” for bone regeneration. We performed nanotopography on titanium plates through alkali and heat (Ti8) treatment to promote human mesenchymal stem cell (hMSC) differentiation. Next, we extracted the sEVs from the hMSC, which were cultured on the nanotopographical Ti plates for 21 days (Ti8-21-sEV). We demonstrated that Ti8-21-sEV had superior pro-osteogenesis ability in vitro and in vivo. RNA sequencing further confirmed that Ti8-21-sEV promote bone regeneration through osteogenic-related pathways, including the PI3K-AKT signaling pathway, MAPK signaling pathway, focal adhesion, and extracellular matrix-receptor interaction. Finally, we decorated the Ti8-21-sEV on a 3D printed porous polyetheretherketone scaffold. The femoral condyle defect model of rabbits was used to demonstrate that Ti8-21-sEV had the best bone ingrowth. In summary, our study demonstrated that the Ti8-21-sEV have memory function by copying the pro-osteogenesis information from the nanotopography. We expect that our study will encourage the discovery of other sEV with morphology memory for tissue regeneration. 展开更多
关键词 Nanotopographic PEEK HMSCS small extracellular vesicles OSTEOGENESIS
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Eliminating the original cargos of glioblastoma cell-derived small extracellular vesicles for efficient drug delivery to glioblastoma with improved biosafety 被引量:1
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作者 Yuhang Guo Guowen Hu +8 位作者 Yuguo Xia HaiYan Li Ji Yuan Juntao Zhang Yu Chen Hua Guo Yunlong Yang Yang Wang Zhifeng Deng 《Bioactive Materials》 SCIE 2022年第10期204-217,共14页
Tumor derived small extracellular vesicles(TsEVs)display a great potential as efficient nanocarriers for chemotherapy because of their intrinsic targeting ability.However,the inherited risks of their original cargos(l... Tumor derived small extracellular vesicles(TsEVs)display a great potential as efficient nanocarriers for chemotherapy because of their intrinsic targeting ability.However,the inherited risks of their original cargos(like loaded proteins or RNAs)from parent cancer cells in tumor progression severely hinder the practical application.In this study,a saponin-mediated cargo elimination strategy was established and practiced in glioblastoma(GBM)cell-derived small extracellular vesicles(GBM-sEVs).A high eliminating efficacy of the cargo molecules was confirmed by systematic analysis of the original proteins and RNAs in GBM-sEVs.In addition,the inherited functions of GBM-sEVs to promote GBM progression vanished after saponin treatment.Moreover,the results of cellular uptake analysis and in vivo imaging analysis demonstrated that saponin treatment preserved the homotypic targeting ability of GBM-sEVs.Thus,we developed an efficient nanocarrier with improved biosafety for GBM suppression.Furthermore,doxorubicin(DOX)transported by the saponin-treated GBM-sEVs(sa-GBM-sEVs)displayed an effective tumor suppression in both subcutaneous and orthotopic GBM models of mouse.Collectively,this study provides a feasible way to avoid the potential protumoral risks of TsEVs and can advance the clinical application of TsEVs in chemotherapy. 展开更多
关键词 Tumor derived small extracellular vesicles Cargo elimination SAPONIN GLIOBLASTOMA Drug delivery
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Phospholipid-grafted PLLA electrospun micro/nanofibers immobilized with small extracellular vesicles from rat adipose mesenchymal stem cells promote wound healing in diabetic rats 被引量:1
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作者 Jing Li Shunshun Yan +4 位作者 Weiju Han Zixuan Dong Junliang Li Qi Wu Xiaoling Fu 《Regenerative Biomaterials》 SCIE EI 2022年第1期827-843,共17页
Small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)can deliver a variety of bioactive factors to create a favorable local microenvironment,thereby holding huge potential in chronic wound repair... Small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)can deliver a variety of bioactive factors to create a favorable local microenvironment,thereby holding huge potential in chronic wound repair.However,free sEVs administrated intravenously or locally are usually cleared rapidly,resulting in an insufficient duration of the efficacy.Thus,strategies that enable optimized retention and release profiles of sEVs at wound sites are desirable.Herein,we fabricated novel functional phosphoethanolamine phospholipid-grafted poly-L-lactic acid micro/nanofibers(DSPE-PLLA)to carry and retain sEVs from rat adipose MSCs,enabling the slow local release of sEVs.Our results showed that sEVs@DSPE-PLLA promoted the proliferation,migration and gene expression(ColⅠ,ColⅢ,TGF-β,α-SMA,HIF-1α)of fibroblasts.It also promoted keratinocyte proliferation.In addition,sEVs@DSPE-PLLA helped polarize macrophages toward the M2 phenotype by increasing the expression of anti-inflammatory genes(Arginase 1,CD 206,IL-10)and inhibiting the expression of pro-inflammatory genes(IL-1β,TNF-α).Further in vivo study in diabetic rat models showed that sEVs@DSPE-PLLA improved the wound-healing process by alleviating the inflammatory responses,stimulating cell proliferation,collagen deposition and angiogenesis.These results highlight the potential of using DSPE-grafted scaffolds for extracellular vesicle immobilization and suggest sEVs@DSPE-PLLA micro/nanofibers as promising functional wound dressings for diabetic wounds. 展开更多
关键词 chronic wound healing small extracellular vesicles sustained release DSPE-PLLA fibers
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Effects of extracellular vesicles from mesenchymal stem cells on oxygen-glucose deprivation/reperfusioninduced neuronal injury 被引量:8
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作者 Shuang-shuang Gu Xiu-wen Kang +4 位作者 Jun Wang Xiao-fang Guo Hao Sun Lei Jiang Jin-song Zhang 《World Journal of Emergency Medicine》 SCIE CAS CSCD 2021年第1期61-67,共7页
BACKGROUND: Small extracellular vesicles (sEVs) from bone marrow mesenchymal stemcells (BMSCs) have shown therapeutic potential for cerebral ischemic diseases. However, themechanisms by which BMSC-derived sEVs (BMSC-s... BACKGROUND: Small extracellular vesicles (sEVs) from bone marrow mesenchymal stemcells (BMSCs) have shown therapeutic potential for cerebral ischemic diseases. However, themechanisms by which BMSC-derived sEVs (BMSC-sEVs) protect neurons against cerebral ischemia/reperfusion (I/R) injury remain unclear. In this study, we explored the neuroprotective effects ofBMSC-sEVs in the primary culture of rat cortical neurons exposed to oxygen-glucose deprivation andreperfusion (OGD/R) injury.METHODS: The primary cortical neuron OGD/R model was established to simulate the processof cerebral I/R in vitro. Based on this model, we examined whether the mechanism through whichBMSC-sEVs could rescue OGD/R-induced neuronal injury.RESULTS: BMSC-sEVs (20 μg/mL, 40 μg/mL) significantly decreased the reactive oxygenspecies (ROS) productions, and increased the activities of superoxide dismutase (SOD) and glutathioneperoxidase (GPx). Additionally, BMSC-sEVs prevented OGD/R-induced neuronal apoptosis in vivo, asindicated by increased cell viability, reduced lactate dehydrogenase (LDH) leakage, decreased terminaldeoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining-positivecells, down-regulated cleaved caspase-3, and up-regulated Bcl-2/Bax ratio. Furthermore, Westernblot and flow cytometry analysis indicated that BMSC-sEV treatment decreased the expression ofphosphorylated calcium/calmodulin-dependent kinase II (p-CaMK II)/CaMK II, suppressed the increaseof intracellular calcium concentration ([Ca2+]i) caused by OGD/R in neurons.CONCLUSIONS: These results demonstrate that BMSC-sEVs have signifi cant neuroprotectiveeff ects against OGD/R-induced cell injury by suppressing oxidative stress and apoptosis, and Ca2+/CaMK II signaling pathways may be involved in this process. 展开更多
关键词 Oxygen-glucose deprivation and reperfusion Cortical neurons Oxidative stress small extracellular vesicles
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FUS-mediated HypEVs: Neuroprotective effects against ischemic stroke 被引量:1
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作者 Yousheng Wu Xiaoxiong Huang +7 位作者 Zefeng Tan Jiankun Zang Min Peng Niu He Tao Zhang Hongcheng Mai Anding Xu Dan Lu 《Bioactive Materials》 SCIE CSCD 2023年第11期196-213,共18页
Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sE... Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis. 展开更多
关键词 Hypoxia FUS Neuron-derived small extracellular vesicle NEUROPROTECTION Mitochondrial mRNA
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