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
Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent bioc...Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.展开更多
Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In soli...Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In solid tumors,angiogenesis supports growth,nutrient delivery,waste removal,and metastasis.Tumors can induce angiogenesis through proangiogenic factors including VEGF,FGF-2,PDGF,angiopoietins,HGF,TNF,IL-6,SCF,tryptase,and chymase.This balance is disrupted in tumors,and extracellular vesicles(EVs)contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells(ECs).Malignant melanoma,a particular type of skin cancer,accounts for only 1%of skin cancer cases but more than 75%of deaths.Its incidence has risen significantly,with a 40%increase between 2012 and 2022,especially in fair-skinned populations.Advanced metastatic stages have a high mortality due to delayed diagnosis.This review examines the molecular basis of angiogenesis in melanoma,focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
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
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–b...Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.展开更多
Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with ...Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.展开更多
Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem ce...Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.展开更多
The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles ...The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles secreted by cells that play a crucial role in intercellular communication due to their diverse cargo.Among these,brain-derived extracellular vesicles,which are secreted by various brain cells such as neurons,glial cells,and Schwann cells,have garnered increasing attention.They serve as a promising tool for elucidating Parkinson's disease pathogenesis and for advancing diagnostic and therapeutic strategies.This review highlights the recent advancements in our understanding of brain-derived extracellular vesicles released into the blood and their role in the pathogenesis of Parkinson's disease,with specific emphasis on their involvement in the aggregation and spread of alpha-synuclein.Brain-derived extracellular vesicles contribute to disease progression through multiple mechanisms,including autophagy-lysosome dysfunction,neuroinflammation,and oxidative stress,collectively driving neurodegeneration in Parkinson's disease.Their application in Parkinson's disease diagnosis is a primary focus of this review.Recent studies have demonstrated that brainderived extracellular vesicles can be isolated from peripheral blood samples,as they carryα-synuclein and other key biomarkers such as DJ-1 and various micro RNAs.These findings highlight the potential of brain-derived extracellular vesicles,not only for the early diagnosis of Parkinson's disease but also for disease progression monitoring and differential diagnosis.Additionally,an overview of explorations into the potential therapeutic applications of brain-derived extracellular vesicles for Parkinson's disease is provided.Therapeutic strategies targeting brain-derived extracellular vesicles involve modulating the release and uptake of pathological alpha-synuclein-containing brain-derived extracellular vesicles to inhibit the spread of the protein.Moreover,brain-derived extracellular vesicles show immense promise as therapeutic delivery vehicles capable of transporting drugs into the central nervous system.Importantly,brain-derived extracellular vesicles also play a crucial role in neural regeneration by promoting neuronal protection,supporting axonal regeneration,and facilitating myelin repair,further enhancing their therapeutic potential in Parkinson's disease and other neurological disorders.Further clarification is needed of the methods for identifying and extracting brain-derived extracellular vesicles,and large-scale cohort studies are necessary to validate the accuracy and specificity of these biomarkers.Future research should focus on systematically elucidating the unique mechanistic roles of brain-derived extracellular vesicles,as well as their distinct advantages in the clinical translation of methods for early detection and therapeutic development.展开更多
Introduction:One of the main events that regulate a cell’s well-being is cell-to-cell communication.This intercellular mechanism of information transfer is often mediated by vesicular trafficking.Mitochondrial-derive...Introduction:One of the main events that regulate a cell’s well-being is cell-to-cell communication.This intercellular mechanism of information transfer is often mediated by vesicular trafficking.Mitochondrial-derived vesicles(MDVs)are an emerging subpopulation of extracellular vesicle(EV)first discovered in 2008 that allow mitochondria to communicate with their surroundings.展开更多
Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellula...Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B.Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B,thereby regulating tooth development.An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice.In conclusion,this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization,which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.展开更多
Extracellular vesicles(EVs)have arisen as potential therapeutic tools in managing infectious diseases because EVs can regulate cell-to-cell signaling,function as drug transport mechanisms,and influence immune reaction...Extracellular vesicles(EVs)have arisen as potential therapeutic tools in managing infectious diseases because EVs can regulate cell-to-cell signaling,function as drug transport mechanisms,and influence immune reactions.They are obtained from a myriad of sources,such as plants,humans,and animal cells.EVs like exosomes and ectosomes can be utilized in their native form as therapeutics or engineered to encompass antimicrobials,vaccines,and oligonucleotides of interest with a targeted delivery strategy.An in-depth understanding of host-pathogen dynamics provides a solid foundation for exploiting its full potential in therapeutics against infectious diseases.This review mainly offers an extensive summary of EVs,comprising their various origins,formations,and pathogen relationships.It further provides insights into the various techniques utilized in isolating and engineering these vesicles to target infectious diseases and how challenges involving large-scale production and cargo loading efficiency should be addressed for clinical application.Finally,preclinical and clinical implementations of EVs derived from animals,plants,and microorganisms are elucidated,stressing their promise for designing innovative antimicrobial approaches.展开更多
Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and in...Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and inflammatory cascade.While IDD naturally progresses with age,some factors such as mechanical trauma,lifestyle choices,and genetic abnormalities can elevate the risk of symptomatic disease progression.Current treatments,including pharmacological and surgical interventions,fail to halt disease progression or restore IDD function.Although biological therapies have been evaluated,their effectiveness in reversing long-term disc degeneration remains inconsistent.Mesenchymal stem cellbased therapies have demonstrated potential for IDD regeneration but are hindered by biological limitations,ethical issues,etc.To date,mesenchymal stem cell-derived extracellular vesicles(EVs)have emerged as promising therapeutic agents for regeneration and anti-inflammation.Their therapeutic effects are attributed to several mechanisms,such as the induction of regenerative phenotype,apoptosis mitigation,and immunomodulation.In addition,the abundance of microRNAs within EVs play a crucial role in modulating the disc degeneration.Due to the problems in clinical use,however,the efficiency of the EVs should be overcome further by optimizing cell culture conditions,engineering them to deliver drugs and targeting molecules,etc.展开更多
Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplanta...Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.展开更多
Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtyp...Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.展开更多
BACKGROUND India has the highest tuberculosis(TB)burden in the world.Of the estimated annual 10 million TB cases,features of extra pulmonary TB are evident in up to 45%.Urogenital TB(UGTB)accounts for approximately 20...BACKGROUND India has the highest tuberculosis(TB)burden in the world.Of the estimated annual 10 million TB cases,features of extra pulmonary TB are evident in up to 45%.Urogenital TB(UGTB)accounts for approximately 20%of those cases.The lack of non-sputum based diagnostic tools continue to hinder efforts to reduce the burden of UGTB.MicroRNAs(miRNAs)play a crucial role in biological pathways and can be used as a potential biomarker for TB.We evaluated urinary extracellular vesicles(uEVs)as non-invasive source to explore miRNAs with biomarker potential for UGTB.AIM To evaluate the potential of miRNA-155-5p,miRNA-26a-5p and miRNA-29a-3p in uEVs to diagnose UGTB in adults.METHODS uEV characterization was done using nanoparticle tracking analysis and flow cytometry.Quantitative reverse transcriptase polymerase chain reaction(qRTPCR)for urinary uEV-miRNAs were carried out in samples from patients with suspected UGTB,or Urinary tract infections[UTI,disease controls(DC)]and healthy controls(HCs)(n=20/group).U6 was used to normalize the qRT-PCR data.Receivers operating characteristic curves was used to calculate the diagnostic accuracy of uEV-miRNAs to differentiate UGTB from controls(DC and HCs).RESULTS uEVs from UGTB or UTI patients had higher mean size,and also lower proportion of CD63 positive vesicles as compared to HC’s uEVs.Between UTI and UGTB,the mean size of uEVs was significantly higher in UTI cases.qRT-PCR analysis revealed a significantly lower abundance of miRNA-155-5p and miRNA-26a-5p in uEVs from UGTB relative to UTI(P value=0.004)and HC(P value=0.009)respectively n=20/group).While,miRNA-29a-3p was higher in abundance in both UGTB and HCs’uEV,relative to uEVs from UTI cases(P values=0.004 and 0.002 respectively,n=20/group).Moreover,miRNA-155-5p[area under curve(AUC)=0.88,P≤0.0001]and miRNA-29a-3p(AUC=0.76,P value=0.005)had optimal diagnostic accuracy to differentiate UGTB from DC(n=20/groups)with a likelihood ratio of 5.2 and 4.3,respectively through receivers operating characteristic curve.While,miRNA-155-5p(AUC=0.68,P value=0.05)and miRNA-26a-5p(AUC=0.78,P value=0.002)had optimal diagnostic accuracy to differentiate UGTB from HCs with a likelihood ratio of>2.CONCLUSION The differential expression of uEV-miRNAs,miRNA-155-5p and miRNA-29a-3p in UTGB and UTI cases hold promise in the specific diagnosis of UGTB.Further studies in large cohort are,however,needed to confirm the diagnostic accuracy of these uEV-miRNAs.展开更多
Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replace...Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replacement therapy,have limited clinical application because of their drawbacks,and more methods need to be developed.In the current study,the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles(h UCMSC-EVs)were investigated in a cisplatin(CDDP)-induced POI mouse model and a human granulosa cell(GC)line.The results showed that h UCMSC-EVs significantly attenuated body weight loss,ovarian weight loss,ovary atrophy,and follicle loss in moderate-dose(1.5 mg/kg)CDDP-induced POI mice,similar to the effects observed with h UCMSCs.We further found that the h UCMSCEVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic mi RNA levels in GCs,thereby downregulating the m RNA levels of multiple pro-apoptotic genes.In general,our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy,considering effective rescue of the oncotherapy-induced ovarian damage with h UCMSC-EVs.Additionally,multiple mi RNAs in h UCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis,thereby restoring ovarian function and improving the life quality of female cancer patients.展开更多
Microneedles(MNs)have been extensively investigated for transdermal delivery of large-sized drugs,including proteins,nucleic acids,and even extracellular vesicles(EVs).However,for their sufficient skin penetration,con...Microneedles(MNs)have been extensively investigated for transdermal delivery of large-sized drugs,including proteins,nucleic acids,and even extracellular vesicles(EVs).However,for their sufficient skin penetration,conventional MNs employ long needles(≥600μm),leading to pain and skin irritation.Moreover,it is critical to stably apply MNs against complex skin surfaces for uniform nanoscale drug delivery.Herein,a dually amplified transdermal patch(MN@EV/SC)is developed as the stem cell-derived EV delivery platform by hierarchically integrating an octopusinspired suction cup(SC)with short MNs(≤300μm).While leveraging the suction effect to induce nanoscale deformation of the stratum corneum,MN@EV/SC minimizes skin damage and enhances the adhesion of MNs,allowing EV to penetrate deeper into the dermis.When MNs of various lengths are applied to mouse skin,the short MNs can elicit comparable corticosterone release to chemical adhesives,whereas long MNs induce a prompt stress response.MN@EV/SC can achieve a remarkable penetration depth(290μm)for EV,compared to that of MN alone(111μm).Consequently,MN@EV/SC facilitates the revitalization of fibroblasts and enhances collagen synthesis in middle-aged mice.Overall,MN@EV/SC exhibits the potential for skin regeneration by modulating the dermal microenvironment and ensuring patient comfort.展开更多
Objective Size distribution is an important biophysical property of extracellular vesicles(EVs).EVs include small EVs(s-EVs)and large EVs(l-EVs)by size.Differential ultracentrifugation(dUC)is widely used to separate E...Objective Size distribution is an important biophysical property of extracellular vesicles(EVs).EVs include small EVs(s-EVs)and large EVs(l-EVs)by size.Differential ultracentrifugation(dUC)is widely used to separate EVs from biofluids,but it can precipitate large impurity particles.Dynamic light scattering(DLS)is a simple and fast method for analyzing the size distribution of EVs.However,this approach is nonideal for heterogeneous and polydisperse samples since a small quantity of large impurity particles can markedly disturb the DLS results.Here,we developed a simple method to improve the reliability of DLS measurements.Methods Plasma was obtained from 13 volunteers.The plasma was first processed by dUC to obtain crude l-EVs.The crude l-EVs were filtered with syringe filters(pore size of 1μm and membrane material of hydrophilic polyvinylidene fluoride(PVDF))to remove large impurity particles from l-EVs.The size distributions of the crude l-EVs and filtered l-EVs were measured via DLS.Results After the samples were filtered,the coefficients of variation of the hydrodynamic radius and Peak 1 intensity of the filtered l-EVs decreased from 20.39%(12.76–28.96%)and 20.44%(14.58–28.32%)to 3.05%(1.79–4.72%)and 3.43%(1.76–5.88%),respectively,compared with those of the crude l-EVs.Conclusion These findings suggest that filtration can effectively separate circulating l-EVs in plasma to remove large impurity particles and make samples suitable for characterization by DLS.Our findings provide a simple method to improve precision via DLS to measure the size distribution of EVs.展开更多
Depression is a prevalent mental disorder that affects numerous individuals,manifesting as persistent anhedonia,sadness,and hopelessness.Despite extensive research,the exact causes and optimal treatment approaches for...Depression is a prevalent mental disorder that affects numerous individuals,manifesting as persistent anhedonia,sadness,and hopelessness.Despite extensive research,the exact causes and optimal treatment approaches for depression remain unclear.Extracellular vesicles(EVs),which carry biological molecules such as proteins,lipids,nucleic acids,and metabolites,have emerged as crucial players in both pathological and physiological processes.EVs derived from various sources exert distinct effects on depression.Specifically,EVs released by neurons,astrocytes,microglia,oligodendrocytes,immune cells,stem cells,and even bacteria contribute to the pathogenesis of depression.Moreover,there is growing interest in potential of EVs as diagnostic and therapeutic tools for depression.This review provides a comprehensive overview of recent research on EVs from different sources,their roles in depression,and their potential clinical applications.展开更多
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘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.
基金supported by the grants from University of Macao,China,Nos.MYRG2022-00221-ICMS(to YZ)and MYRG-CRG2022-00011-ICMS(to RW)the Natural Science Foundation of Guangdong Province,No.2023A1515010034(to YZ)。
文摘Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.
基金supported by grants from the Jagiellonian University,Poland(N18/DBS/000007)the Polish National Science Centre(2018/31/N/NZ4/03787).
文摘Angiogenesis,the expansion of pre-existing vascular networks,is crucial for normal organ growth and tissue repair,but is also involved in various pathologies,including inflammation,ischemia,diabetes,and cancer.In solid tumors,angiogenesis supports growth,nutrient delivery,waste removal,and metastasis.Tumors can induce angiogenesis through proangiogenic factors including VEGF,FGF-2,PDGF,angiopoietins,HGF,TNF,IL-6,SCF,tryptase,and chymase.This balance is disrupted in tumors,and extracellular vesicles(EVs)contribute to this by transferring proangiogenic factors and increasing their expression in endothelial cells(ECs).Malignant melanoma,a particular type of skin cancer,accounts for only 1%of skin cancer cases but more than 75%of deaths.Its incidence has risen significantly,with a 40%increase between 2012 and 2022,especially in fair-skinned populations.Advanced metastatic stages have a high mortality due to delayed diagnosis.This review examines the molecular basis of angiogenesis in melanoma,focusing on melanoma-derived EVs and their possible use in new antiangiogenic therapies.
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
基金supported by the National Natural Science Foundation of China,No.82271114the Natural Science Foundation of Zhejiang Province of China,No.LZ22H120001(both to ZLC).
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82171363,82371381(to PL),82171458(to XJ)Key Research and Development Project of Shaa nxi Province,Nos.2024SF-YBXM-404(to KY)。
文摘Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.
基金supported by grants from the Spanish Ministry of Health-PNSD(2019-I039 and 2023-I024)(to MP)FEDER/Ministerio de Ciencia e Innovación-Agencia Estatal de Investigación PID2021-1243590B-I100(to VMM)+2 种基金GVA(CIAICO/2021/203)(to MP)the Primary Addiction Care Research Network(RD21/0009/0005)(to MP)a predoctoral fellowship from the Generalitat Valenciana(ACIF/2021/338)(to CPC).
文摘Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage.Mesenchymal stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice.Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking.We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent mice.Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways.Taken together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.
基金supported by the National Nature Science Foundation of China,No.81471308(to JL)the Innovative Leading Talents of Liaoning Province,No.XLYC1902031(to JL)+2 种基金Science and Technology Projects in Liaoning Province,No.2022-BS-238(to CH)Young Top Talents of Liaoning Province,No.XLYC1907009(to LW)Dalian Science and Technology Innovation Fund,No.2018J11CY025(to JL)。
文摘Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of China,No.822712782019 Wuhan Huanghe Talents Program+3 种基金2020 Wuhan Medical Research Project,No.20200206010123032021 Hubei Youth Top-notch Talent Training Program2022 Outstanding Youth Project of Natural Science Foundation of Hubei Province,No.2022CFA106Medical Research Program of Huatongguokang,No.2023HT036(all to NX)。
文摘The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles secreted by cells that play a crucial role in intercellular communication due to their diverse cargo.Among these,brain-derived extracellular vesicles,which are secreted by various brain cells such as neurons,glial cells,and Schwann cells,have garnered increasing attention.They serve as a promising tool for elucidating Parkinson's disease pathogenesis and for advancing diagnostic and therapeutic strategies.This review highlights the recent advancements in our understanding of brain-derived extracellular vesicles released into the blood and their role in the pathogenesis of Parkinson's disease,with specific emphasis on their involvement in the aggregation and spread of alpha-synuclein.Brain-derived extracellular vesicles contribute to disease progression through multiple mechanisms,including autophagy-lysosome dysfunction,neuroinflammation,and oxidative stress,collectively driving neurodegeneration in Parkinson's disease.Their application in Parkinson's disease diagnosis is a primary focus of this review.Recent studies have demonstrated that brainderived extracellular vesicles can be isolated from peripheral blood samples,as they carryα-synuclein and other key biomarkers such as DJ-1 and various micro RNAs.These findings highlight the potential of brain-derived extracellular vesicles,not only for the early diagnosis of Parkinson's disease but also for disease progression monitoring and differential diagnosis.Additionally,an overview of explorations into the potential therapeutic applications of brain-derived extracellular vesicles for Parkinson's disease is provided.Therapeutic strategies targeting brain-derived extracellular vesicles involve modulating the release and uptake of pathological alpha-synuclein-containing brain-derived extracellular vesicles to inhibit the spread of the protein.Moreover,brain-derived extracellular vesicles show immense promise as therapeutic delivery vehicles capable of transporting drugs into the central nervous system.Importantly,brain-derived extracellular vesicles also play a crucial role in neural regeneration by promoting neuronal protection,supporting axonal regeneration,and facilitating myelin repair,further enhancing their therapeutic potential in Parkinson's disease and other neurological disorders.Further clarification is needed of the methods for identifying and extracting brain-derived extracellular vesicles,and large-scale cohort studies are necessary to validate the accuracy and specificity of these biomarkers.Future research should focus on systematically elucidating the unique mechanistic roles of brain-derived extracellular vesicles,as well as their distinct advantages in the clinical translation of methods for early detection and therapeutic development.
基金supported by project Emerging Infectious Diseases One Health Basic and Translational Research Actions addressing Unmet Needs on Emerging Infectious Diseases,INF-ACT,Spoke 1 and Spoke 5,Project number PE00000007,CUP B53C20040570005(to PP and DN).
文摘Introduction:One of the main events that regulate a cell’s well-being is cell-to-cell communication.This intercellular mechanism of information transfer is often mediated by vesicular trafficking.Mitochondrial-derived vesicles(MDVs)are an emerging subpopulation of extracellular vesicle(EV)first discovered in 2008 that allow mitochondria to communicate with their surroundings.
基金supported by the National Natural Science Foundation of China(No.82071078,82370939)the Shaanxi Provincial High-level Talent Program and Young Talent Support Plan of Xi’an Jiaotong University.
文摘Tissue interactions play a crucial role in tooth development.Notably,extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential.Here,we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B.Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B,thereby regulating tooth development.An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice.In conclusion,this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization,which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.
基金funded by the National Science Foundation grant(IOS-1900377),received by QLM and EPSCoR GRSP Round 19 grant received by SVTW.
文摘Extracellular vesicles(EVs)have arisen as potential therapeutic tools in managing infectious diseases because EVs can regulate cell-to-cell signaling,function as drug transport mechanisms,and influence immune reactions.They are obtained from a myriad of sources,such as plants,humans,and animal cells.EVs like exosomes and ectosomes can be utilized in their native form as therapeutics or engineered to encompass antimicrobials,vaccines,and oligonucleotides of interest with a targeted delivery strategy.An in-depth understanding of host-pathogen dynamics provides a solid foundation for exploiting its full potential in therapeutics against infectious diseases.This review mainly offers an extensive summary of EVs,comprising their various origins,formations,and pathogen relationships.It further provides insights into the various techniques utilized in isolating and engineering these vesicles to target infectious diseases and how challenges involving large-scale production and cargo loading efficiency should be addressed for clinical application.Finally,preclinical and clinical implementations of EVs derived from animals,plants,and microorganisms are elucidated,stressing their promise for designing innovative antimicrobial approaches.
基金Supported by 2024 Yeungnam University Grant,No.224A480005.
文摘Intervertebral disc degeneration(IDD)results from an imbalance within the intervertebral disc,leading to alterations in extracellular matrix composition,loss of nucleus pulposus cells,increased oxidative stress,and inflammatory cascade.While IDD naturally progresses with age,some factors such as mechanical trauma,lifestyle choices,and genetic abnormalities can elevate the risk of symptomatic disease progression.Current treatments,including pharmacological and surgical interventions,fail to halt disease progression or restore IDD function.Although biological therapies have been evaluated,their effectiveness in reversing long-term disc degeneration remains inconsistent.Mesenchymal stem cellbased therapies have demonstrated potential for IDD regeneration but are hindered by biological limitations,ethical issues,etc.To date,mesenchymal stem cell-derived extracellular vesicles(EVs)have emerged as promising therapeutic agents for regeneration and anti-inflammation.Their therapeutic effects are attributed to several mechanisms,such as the induction of regenerative phenotype,apoptosis mitigation,and immunomodulation.In addition,the abundance of microRNAs within EVs play a crucial role in modulating the disc degeneration.Due to the problems in clinical use,however,the efficiency of the EVs should be overcome further by optimizing cell culture conditions,engineering them to deliver drugs and targeting molecules,etc.
基金supported by the National Natural Science Foundation of China,Nos.82271132(to YL),82101167(to BB)the Natural Science Foundation of Chongqing,Nos.CSTB2022NSCQ-MSX0020(to BB),cstc2019jcyj-msxmX0473(to FC).
文摘Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone.Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles.Small extracellular vesicles derived from bone marrow mesenchymal stem cells,which offer low immunogenicity,minimal tumorigenic risk,and ease of transportation,have been utilized in the treatment of various neurological diseases.These vesicles exhibit various activities,including anti-inflammatory actions,promotion of tissue repair,and immune regulation.Therefore,novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration.In this study,we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats,a genetic model of retinal degeneration.Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats.The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival,migration,and differentiation of the exogenous retinal progenitor cells.Concurrently,these small extracellular vesicles inhibited the activation of regional microglia,promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina,and facilitated their differentiation into photoreceptors and bipolar cells.These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.
基金supported by the Bridging Grant from Universiti Sains Malaysia (R501LR-RND003–0000001319–0000)funding through the Fundamental Research Grant Scheme (FRGS/1/2020/TK0/USM/02/32–6171275) awarded by the Ministry of Higher Education Malaysia
文摘Current treatments for glioblastoma face challenges such as the blood-brain barrier and lack of targeted therapy,compounded by the aggressive nature,high invasiveness,and heterogeneity of the disease.Exosomes,a subtype of extracellular vesicles are emerging as promising nanocarrier drug delivery systems to address these limitations.Exosomes released by all cell types can be easily obtained and modified as delivery vehicles or therapeutic agents.A systematic review was conducted to evaluate various methods for exosome isolation,characterization,engineering or modification,drug loading and delivery efficiency,including exosome biodistribution and treatment efficacy.A search of four databases for in vitro and in vivo studies(2000–,2023)identified 6165 records,of which 23 articles were found eligible and included for analyses.Most studies applied ultracentrifugation(UC)for exosomes isolation.Cancer cell lines being the most frequently used source of exosomes,followed by stem cells.The incubation approach was predominantly utilized to modify exosomes for drug loading.In vivo analysis showed that exosome biodistribution was primarily concentrated in the brain region,peaking in the first 6 h and remained moderately high.Compared to native exosomes and untreated control groups,utilizing modified native exosomes(cargo loaded)for treating glioblastoma disease models led to more pronounced suppression of tumor growth and proliferation,enhanced stimulation of immune response and apoptosis,effective restoration of drug chemosensitivity,increased anti-tumor effect and prolonged survival rates.Modified exosomes whether through incubation,sonication,transfection,freeze-thawing or their combination,improve targeted delivery and therapeutic efficacy against glioblastoma.
基金Supported by the Indian Council of Medical Research,No.Coord/7(1)/CARE-KD/18-NCD-II.
文摘BACKGROUND India has the highest tuberculosis(TB)burden in the world.Of the estimated annual 10 million TB cases,features of extra pulmonary TB are evident in up to 45%.Urogenital TB(UGTB)accounts for approximately 20%of those cases.The lack of non-sputum based diagnostic tools continue to hinder efforts to reduce the burden of UGTB.MicroRNAs(miRNAs)play a crucial role in biological pathways and can be used as a potential biomarker for TB.We evaluated urinary extracellular vesicles(uEVs)as non-invasive source to explore miRNAs with biomarker potential for UGTB.AIM To evaluate the potential of miRNA-155-5p,miRNA-26a-5p and miRNA-29a-3p in uEVs to diagnose UGTB in adults.METHODS uEV characterization was done using nanoparticle tracking analysis and flow cytometry.Quantitative reverse transcriptase polymerase chain reaction(qRTPCR)for urinary uEV-miRNAs were carried out in samples from patients with suspected UGTB,or Urinary tract infections[UTI,disease controls(DC)]and healthy controls(HCs)(n=20/group).U6 was used to normalize the qRT-PCR data.Receivers operating characteristic curves was used to calculate the diagnostic accuracy of uEV-miRNAs to differentiate UGTB from controls(DC and HCs).RESULTS uEVs from UGTB or UTI patients had higher mean size,and also lower proportion of CD63 positive vesicles as compared to HC’s uEVs.Between UTI and UGTB,the mean size of uEVs was significantly higher in UTI cases.qRT-PCR analysis revealed a significantly lower abundance of miRNA-155-5p and miRNA-26a-5p in uEVs from UGTB relative to UTI(P value=0.004)and HC(P value=0.009)respectively n=20/group).While,miRNA-29a-3p was higher in abundance in both UGTB and HCs’uEV,relative to uEVs from UTI cases(P values=0.004 and 0.002 respectively,n=20/group).Moreover,miRNA-155-5p[area under curve(AUC)=0.88,P≤0.0001]and miRNA-29a-3p(AUC=0.76,P value=0.005)had optimal diagnostic accuracy to differentiate UGTB from DC(n=20/groups)with a likelihood ratio of 5.2 and 4.3,respectively through receivers operating characteristic curve.While,miRNA-155-5p(AUC=0.68,P value=0.05)and miRNA-26a-5p(AUC=0.78,P value=0.002)had optimal diagnostic accuracy to differentiate UGTB from HCs with a likelihood ratio of>2.CONCLUSION The differential expression of uEV-miRNAs,miRNA-155-5p and miRNA-29a-3p in UTGB and UTI cases hold promise in the specific diagnosis of UGTB.Further studies in large cohort are,however,needed to confirm the diagnostic accuracy of these uEV-miRNAs.
基金Financial support for the current study was provided by the grant from"Blue Engineering"Excellent Young Teacher Foundation in Colleges and Universities of Jiangsu Province(Grant No.KY101R202207 to Xiaojun Chen)。
文摘Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replacement therapy,have limited clinical application because of their drawbacks,and more methods need to be developed.In the current study,the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles(h UCMSC-EVs)were investigated in a cisplatin(CDDP)-induced POI mouse model and a human granulosa cell(GC)line.The results showed that h UCMSC-EVs significantly attenuated body weight loss,ovarian weight loss,ovary atrophy,and follicle loss in moderate-dose(1.5 mg/kg)CDDP-induced POI mice,similar to the effects observed with h UCMSCs.We further found that the h UCMSCEVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic mi RNA levels in GCs,thereby downregulating the m RNA levels of multiple pro-apoptotic genes.In general,our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy,considering effective rescue of the oncotherapy-induced ovarian damage with h UCMSC-EVs.Additionally,multiple mi RNAs in h UCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis,thereby restoring ovarian function and improving the life quality of female cancer patients.
基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSIT)(No.RS-2023-00256265,RS-2024-00352352,RS-2024-00405818)the Korean Fund for Regenerative Medicine(KFRM)grant funded by the Korea government(the Ministry of Science and ICT,the Ministry of Health&Welfare).(No.25A0102L1)support from the Market-led K-sensor technology program(RS-2022-00154781,Development of large-area wafer-level flexible/stretchable hybrid sensor platform technology for form factor-free highly integrated convergence sensor),funded By the Ministry of Trade,Industry&Energy(MOTIE,Korea).
文摘Microneedles(MNs)have been extensively investigated for transdermal delivery of large-sized drugs,including proteins,nucleic acids,and even extracellular vesicles(EVs).However,for their sufficient skin penetration,conventional MNs employ long needles(≥600μm),leading to pain and skin irritation.Moreover,it is critical to stably apply MNs against complex skin surfaces for uniform nanoscale drug delivery.Herein,a dually amplified transdermal patch(MN@EV/SC)is developed as the stem cell-derived EV delivery platform by hierarchically integrating an octopusinspired suction cup(SC)with short MNs(≤300μm).While leveraging the suction effect to induce nanoscale deformation of the stratum corneum,MN@EV/SC minimizes skin damage and enhances the adhesion of MNs,allowing EV to penetrate deeper into the dermis.When MNs of various lengths are applied to mouse skin,the short MNs can elicit comparable corticosterone release to chemical adhesives,whereas long MNs induce a prompt stress response.MN@EV/SC can achieve a remarkable penetration depth(290μm)for EV,compared to that of MN alone(111μm).Consequently,MN@EV/SC facilitates the revitalization of fibroblasts and enhances collagen synthesis in middle-aged mice.Overall,MN@EV/SC exhibits the potential for skin regeneration by modulating the dermal microenvironment and ensuring patient comfort.
基金National Natural Science Foundation of China(No.82495171,92268202,82270485)National Key R&D Program of China(No.2021YFA0805100)+5 种基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2023-PT320-03)Guangdong Basic and Applied Basic Research Foundation,China(No.2024A1515030041)The Science and Technology Planning Project of Guangdong Province,(No.2023B1212060018)Sun Yat-sen University Basic Research Funds(No.24qnpy354)Clinical Research 5010 Program(No.2014002)Program of National Key Clinical Specialties.
文摘Objective Size distribution is an important biophysical property of extracellular vesicles(EVs).EVs include small EVs(s-EVs)and large EVs(l-EVs)by size.Differential ultracentrifugation(dUC)is widely used to separate EVs from biofluids,but it can precipitate large impurity particles.Dynamic light scattering(DLS)is a simple and fast method for analyzing the size distribution of EVs.However,this approach is nonideal for heterogeneous and polydisperse samples since a small quantity of large impurity particles can markedly disturb the DLS results.Here,we developed a simple method to improve the reliability of DLS measurements.Methods Plasma was obtained from 13 volunteers.The plasma was first processed by dUC to obtain crude l-EVs.The crude l-EVs were filtered with syringe filters(pore size of 1μm and membrane material of hydrophilic polyvinylidene fluoride(PVDF))to remove large impurity particles from l-EVs.The size distributions of the crude l-EVs and filtered l-EVs were measured via DLS.Results After the samples were filtered,the coefficients of variation of the hydrodynamic radius and Peak 1 intensity of the filtered l-EVs decreased from 20.39%(12.76–28.96%)and 20.44%(14.58–28.32%)to 3.05%(1.79–4.72%)and 3.43%(1.76–5.88%),respectively,compared with those of the crude l-EVs.Conclusion These findings suggest that filtration can effectively separate circulating l-EVs in plasma to remove large impurity particles and make samples suitable for characterization by DLS.Our findings provide a simple method to improve precision via DLS to measure the size distribution of EVs.
基金Supported by Gusu Talent program,No.(2023)105Suzhou Science and Technology Development Plan Program,No.SKY2023228+2 种基金Project of Medical Research Fund of Jiangsu Provincial Health Commission,No.Z2023043Suzhou Clinical Medical Center for Mood Disorders,No.Szlcyxzx202109Suzhou Clinical Key Disciplines for Geriatric Psychiatry,No.SZXK202116.
文摘Depression is a prevalent mental disorder that affects numerous individuals,manifesting as persistent anhedonia,sadness,and hopelessness.Despite extensive research,the exact causes and optimal treatment approaches for depression remain unclear.Extracellular vesicles(EVs),which carry biological molecules such as proteins,lipids,nucleic acids,and metabolites,have emerged as crucial players in both pathological and physiological processes.EVs derived from various sources exert distinct effects on depression.Specifically,EVs released by neurons,astrocytes,microglia,oligodendrocytes,immune cells,stem cells,and even bacteria contribute to the pathogenesis of depression.Moreover,there is growing interest in potential of EVs as diagnostic and therapeutic tools for depression.This review provides a comprehensive overview of recent research on EVs from different sources,their roles in depression,and their potential clinical applications.
