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
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
The mechanisms leading to neurological and neurodegenerative diseases are not completely known,and new,more effective,therapeutic treatments are necessary for most neurological pathologies.The treatment of neurologica...The mechanisms leading to neurological and neurodegenerative diseases are not completely known,and new,more effective,therapeutic treatments are necessary for most neurological pathologies.The treatment of neurological and neurodegenerative diseases is complicated due to the blood-brain barrier,which makes it difficult for drugs to access the brain areas in which they must act to improve the pathology.A tool that can help to overcome this difficulty is the use of extracellular vesicles,which can easily cross the blood-brain barrier.The extracellular vesicles are considered a main way of communication between the brain and the rest of the body,with important implications for the physiopathology and therapy of neurological diseases.In recent years,the involvement of microbiota in many neurological pathologies,as well as its possible therapeutic role,has also become evident.A key mediator in the pathologic and beneficial effects of microbiota seems to be the bacterial extracellular vesicles.There is an important communication between the brain and the intestinal microbiota(the gut-brain axis),by which the microbiota influences brain function,impacts on mental health,and plays a role in different neurological and neurodegenerative diseases.The identification of the mechanisms involved in this gut-brain axis is essential to understanding the mechanisms of neurological pathologies and to developing more effective treatments for these diseases.Bacterial extracellular vesicles would play a relevant role in these processes.This review compiles the recent information and evidence on the role of bacterial extracellular vesicles in brain pathologies and on the therapeutic utility of bacterial extracellular vesicles in neurological and neurodegenerative diseases.One advantage of bacterial extracellular vesicles compared to extracellular vesicles derived from other cell types,such as stem cells,is that bacterial extracellular vesicles are generally easier to produce and modify.Bacterial extracellular vesicles may be easily modified to target a specific pathology and/or to enhance its therapeutic efficacy.Although the studies are still scarce,they open a wide field of possibilities for future studies,which will lead to a deeper understanding of the role of microbiota and bacterial extracellular vesicles in neurological pathologies and the underlying mechanisms,as well as to the development of new treatments based on the use of bacterial extracellular vesicles in neurological diseases.展开更多
BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the commo...BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments.AIM To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles(hAFSC-EVs)on the recovery of bladder dysfunction in DMA rats.METHODS Eighty rats were divided into normal control,streptozotocin-induced diabetic rats,diabetic rats subjected to arterial balloon endothelial injury of common iliac artery(DMA),and DMA rats treated with hAFSC-EVs(DMA+hAFSC-EVs).At 4 weeks and 12 weeks after DMA induction,levels of blood glucose,total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,homeostasis model assessment(HOMA)-insulin resistance,and HOMA-βwere measured.Cystometry,common iliac artery wall thickness,and bladder tumor necrosis factor(TNF)-α,interleukin(IL)-6,transforming growth factor(TGF)-β1,Smad3,connective tissue growth factor(CTGF)and fibronectin were also evaluated.RESULTS Bladder weight and blood glucose,triglyceride,HOMA-insulin resistance,common iliac artery intima thickness,voided volume,intercontraction interval,bladder capacity,and mRNA expression of TNF-α,IL-6,TGF-β1,Smad3,CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction,while the HOMA-βlevel decreased at 4 weeks and 12 weeks,and the high-density lipoprotein cholesterol level decreased at 12 weeks.hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose,thickness of common iliac arterial intima,voided volume,intercontraction interval and bladder capacity at 4 weeks.The mRNA expression of TNF-α,TGF-β1,and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks,while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks.CONCLUSION hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction,which is associated with lowered blood glucose levels,reduced arterial wall thickness,and decreased TNF-α,IL-6,TGF-β1,Smad3,and CTGF expression.展开更多
Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesi...Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.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
Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatm...Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatment for clinical use.Recent evidence shows that extracellular vesicles isolated from a variety of stem cells are efficacious in retinal ganglion cell neuroprotection.In this study,we tested the novel extracellular vesicle source of the retinal progenitor R-28 cell line in vitro and in vivo.We isolated and characterized extracellular vesicles from R-28 cells and tested their therapeutic efficacy in terms of retinal ganglion cell survival in vitro and in an in vivo glaucoma model,measuring retinal ganglion cell survival and preservation of their axons.Additionally,we tested extracellular vesicles for their neuroprotective capacity in retinal ganglion cells differentiated from human embryonic stem cells.Finally,we investigated miRNA changes in retinal ganglion cells with R-28 extracellular vesicle treatment,and predicted possible pathways that may be modulated.R-28 extracellular vesicles improved retinal ganglion cell survival but failed to preserve axons significantly.Moreover,the results also illustrated the neuroprotection of R-28 extracellular vesicles on human retinal ganglion cells.Finally,we also showed changes in hsa-miRNA-4443,hsa-miRNA-216a-5p,hsa-let-7e-5p,hsa-miRNA-374b-5p,hsa-miRNA-331-3p,and hsa-miRNA-421 expressions,which may have neuroprotective potential on retinal ganglion cell degeneration.This study will pave the way for miRNA and extracellular vesicle-based neuroprotective therapies for glaucoma.展开更多
Delivery carriers serve as a highly efficient approach for precision nutrition and medicine;however,artificial delivery carriers are prone to triggering the immune response and have the disadvantages of poor stability...Delivery carriers serve as a highly efficient approach for precision nutrition and medicine;however,artificial delivery carriers are prone to triggering the immune response and have the disadvantages of poor stability and low bioavailability.Extracellular vesicles(EVs),nucleus-free biological particles composed of phospholipid bilayers secreted by living cells,are a new generation of targeted delivery carriers.In recent years,an increasing number of species have been reported to contain EVs.Among them,food-derived extracellular vesicles(FDEVs)show outstanding comprehensive properties.FDEVs are considered to have great application potential due to their wide range of sources,high yields,absence of human pathogenic pathogens,and ethical concerns.In this review,the preparation,nomenclature,physicochemical characteristics,and preservation methods of FDEVs are discussed,as well as their potential protein markers,bioactivities,and applications as novel targeted delivery carriers of FDEVs from animals,plants,and microorganisms.We also summarized the adverse consequences of FDEVs in current studies,and put forward the problems and challenges in the process of FDEVs research and commercialization.In short,the importance of FDEVs has been highlighted,and FDEVs have good application prospects as a new class of targeted delivery carriers.The current problems should be paid attention to and actively solved.展开更多
Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated ...Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.展开更多
Background An imbalance in the rumen microbiota caused by high-concentrate diets(HCD)is a significant endogenous trigger of mastitis.However,the underlying mechanisms remain largely unknown.Microbial extracellular ves...Background An imbalance in the rumen microbiota caused by high-concentrate diets(HCD)is a significant endogenous trigger of mastitis.However,the underlying mechanisms remain largely unknown.Microbial extracellular vesicles(mEVs)are critical mediators of microbe-host communication.However,the role of mEVs in rumen microbiota-mediated mastitis has not yet been reported.In this study,we used an HCD-induced rumen microbiota dysbiosis model to investigate the role of mEVs-derived from rumen microbiota in the pathogenesis of mastitis.Results Our results indicate that HCD leads to mastitis and systemic inflammation.Meanwhile,HCD-fed goats exhibited substantial rumen microbiota dysbiosis and the disruption of the rumen barrier.Transplanting rumen microbiota from HCD goats into mice induced both mastitis and systemic inflammation in the recipients.Specifically,HCD increases the production of mEVs carrying microbial DNA,which can translocate across the compromised rumen barrier to the mammary gland,triggering a mammary inflammatory response via activation of the cGAS-STING-NF-κB/NLRP3 pathway.Furthermore,treating mice with mEVs isolated from the rumen fluid of HCD goats directly induced mastitis,whereas depletion of microbial DNA attenuated mEVs-induced mastitis.Conclusion Our findings suggest that HCD induces rumen microbiota dysbiosis and impairs rumen barrier function.This dysfunction leads to an increase in microbial DNA-containing mEVs,which subsequently leak into the mammary gland.Once there,these mEVs activate the cGAS-STING-NF-κB/NLRP3 signaling pathway,ultimately inducing mastitis.This study provides a new perspective on the“rumen microbiota-mammary gland axis”and enhances the understanding of the pathogenesis of mastitis.展开更多
Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration vi...Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration via paracrine signaling;however,their clinical applications are limited by potential risks such as tumorigenesis and xenogeneic immune rejection,which are similar to the risks associated with other stem cell transplantations.The present study therefore focuses on small extracellular vesicles derived from hair follicle neural crest stem cells,which preserve the bioactive properties of the parent cells while avoiding the transplantation-associated risks.In vitro,small extracellular vesicles derived from hair follicle neural crest stem cells significantly enhanced the proliferation,migration,tube formation,and barrier function of perineurial cells,and subsequently upregulated the expression of tight junction proteins.Furthermore,in a rat model of sciatic nerve defects bridged with silicon tubes,treatment with small extracellular vesicles derived from hair follicle neural crest stem cells resulted in higher tight junction protein expression in perineurial cells,thus facilitating neural tissue regeneration.At 10 weeks post-surgery,rats treated with small extracellular vesicles derived from hair follicle neural crest stem cells exhibited improved nerve function recovery and reduced muscle atrophy.Transcriptomic and micro RNA analyses revealed that small extracellular vesicles derived from hair follicle neural crest stem cells deliver mi R-21-5p,which inhibits mothers against decapentaplegic homolog 7 expression,thereby activating the transforming growth factor-β/mothers against decapentaplegic homolog signaling pathway and upregulating hyaluronan synthase 2 expression,and further enhancing tight junction protein expression.Together,our findings indicate that small extracellular vesicles derived from hair follicle neural crest stem cells promote the proliferation,migration,and tight junction protein formation of perineurial cells.These results provide new insights into peripheral nerve regeneration from the perspective of perineurial cells,and present a novel approach for the clinical treatment of peripheral nerve defects.展开更多
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
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
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
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
BACKGROUND Extracellular vesicles derived from mesenchymal stromal cells(MSC-EVs)can be used for anti-aging therapy and treating various aging-related diseases.However,the clinical application of MSC-EVs is still limi...BACKGROUND Extracellular vesicles derived from mesenchymal stromal cells(MSC-EVs)can be used for anti-aging therapy and treating various aging-related diseases.However,the clinical application of MSC-EVs is still limited,mainly due to insufficient in-formation on the preparation process,quality,and mechanism of action of MSC-EVs.To study the biological effects of MSC-EVs in regulating cellular senescence.METHODS In this study,we developed a clinical-grade production process for MSC-EVs and defined the release criteria for products suitable for human use.To support the clinical use of our product as a therapeutic agent,we performed efficacy assays to evaluate the anti-aging capacity of MSC-EVs in vitro and in vivo.RESULTS The functional analysis results revealed that MSC-EVs significantly reduced the levels of senescence-associatedβ-galactosidase,matrix metallopeptidase 1,P21,and interleukin-1βand increased the level of collagen I in a naturally aged cell model of human dermal fibroblasts.Similarly,treatment with MSC-EVs effectively improved D-gal-induced subacute aging in mice,aging-related histopathological changes,oxidative stress,and aging-related gene expression.CONCLUSION These findings indicate that MSC-EVs can partially alleviate D-gal-induced senescence by reducing oxidative stress and regulating metabolism.Overall,these findings strongly suggest that MSC-EVs hold promise for aging therapy.展开更多
Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesic...Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesicles(EVs),including exosomes,have emerged as promising therapeutic tools for various pathological conditions,especially cancer.Evidence indicates that changes in the quantity and composition of EVs can influence the immunosuppressive tumor microenvironment,potentially affecting the effectiveness of immunotherapy.Exploiting EVs for immune sensitization has generated significant clinical interest.This review provides an in-depth understanding of the origin of EVs,their therapeutic applications(such as drug delivery nanoplatforms and cancer immunotherapies,including vaccines),diagnostic potential as tumor biomarkers,ongoing EV-based clinical trials,and the challenges encountered in EV-based cancer immunotherapy.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
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funded by the Ministerio de Ciencia e Innovación Spain(PID2020-113388RB-I00,AEI/10.13039/501100011033)Consellería de Innovación,Universidades,Ciencia y Sociedad Digital,Generalitat Valenciana(CIPROM/2021/082)+2 种基金co-funded with European Regional Development Funds(ERDF)(PID2020-113388RB-I00,and CIPROM/2021/082)PID2022-136874OB-C33 from MCIN/AEI/10.13039/501100011033by the European Union NextGenerationEU/PRTR(to VF).
文摘The mechanisms leading to neurological and neurodegenerative diseases are not completely known,and new,more effective,therapeutic treatments are necessary for most neurological pathologies.The treatment of neurological and neurodegenerative diseases is complicated due to the blood-brain barrier,which makes it difficult for drugs to access the brain areas in which they must act to improve the pathology.A tool that can help to overcome this difficulty is the use of extracellular vesicles,which can easily cross the blood-brain barrier.The extracellular vesicles are considered a main way of communication between the brain and the rest of the body,with important implications for the physiopathology and therapy of neurological diseases.In recent years,the involvement of microbiota in many neurological pathologies,as well as its possible therapeutic role,has also become evident.A key mediator in the pathologic and beneficial effects of microbiota seems to be the bacterial extracellular vesicles.There is an important communication between the brain and the intestinal microbiota(the gut-brain axis),by which the microbiota influences brain function,impacts on mental health,and plays a role in different neurological and neurodegenerative diseases.The identification of the mechanisms involved in this gut-brain axis is essential to understanding the mechanisms of neurological pathologies and to developing more effective treatments for these diseases.Bacterial extracellular vesicles would play a relevant role in these processes.This review compiles the recent information and evidence on the role of bacterial extracellular vesicles in brain pathologies and on the therapeutic utility of bacterial extracellular vesicles in neurological and neurodegenerative diseases.One advantage of bacterial extracellular vesicles compared to extracellular vesicles derived from other cell types,such as stem cells,is that bacterial extracellular vesicles are generally easier to produce and modify.Bacterial extracellular vesicles may be easily modified to target a specific pathology and/or to enhance its therapeutic efficacy.Although the studies are still scarce,they open a wide field of possibilities for future studies,which will lead to a deeper understanding of the role of microbiota and bacterial extracellular vesicles in neurological pathologies and the underlying mechanisms,as well as to the development of new treatments based on the use of bacterial extracellular vesicles in neurological diseases.
基金the Ministry of Science and Technology Taiwan,No.MOST 109-2314-B-182A-091,No.NSTC 112-2314-B-182A-062, No.NSTC 113-2314-B-182A-125.
文摘BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments.AIM To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles(hAFSC-EVs)on the recovery of bladder dysfunction in DMA rats.METHODS Eighty rats were divided into normal control,streptozotocin-induced diabetic rats,diabetic rats subjected to arterial balloon endothelial injury of common iliac artery(DMA),and DMA rats treated with hAFSC-EVs(DMA+hAFSC-EVs).At 4 weeks and 12 weeks after DMA induction,levels of blood glucose,total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,homeostasis model assessment(HOMA)-insulin resistance,and HOMA-βwere measured.Cystometry,common iliac artery wall thickness,and bladder tumor necrosis factor(TNF)-α,interleukin(IL)-6,transforming growth factor(TGF)-β1,Smad3,connective tissue growth factor(CTGF)and fibronectin were also evaluated.RESULTS Bladder weight and blood glucose,triglyceride,HOMA-insulin resistance,common iliac artery intima thickness,voided volume,intercontraction interval,bladder capacity,and mRNA expression of TNF-α,IL-6,TGF-β1,Smad3,CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction,while the HOMA-βlevel decreased at 4 weeks and 12 weeks,and the high-density lipoprotein cholesterol level decreased at 12 weeks.hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose,thickness of common iliac arterial intima,voided volume,intercontraction interval and bladder capacity at 4 weeks.The mRNA expression of TNF-α,TGF-β1,and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks,while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks.CONCLUSION hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction,which is associated with lowered blood glucose levels,reduced arterial wall thickness,and decreased TNF-α,IL-6,TGF-β1,Smad3,and CTGF expression.
基金supported by the Spanish Ministry of Health‐Plan Nacional sobre Drogas(2023‐I024)the the Ministry of Science,Innovation and Universities/State ResearchAgency/10.13039/501100011033(PID2023-146865OB-I00)+2 种基金Generalitat Valenciana(CIAICO/2021/203)the Primary Addiction Care Research Network(RD21/0009/0005)FEDER Funds,GVA.
文摘Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy;indeed,micro(mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways.Chronic alcohol consumption leads to neuroinflammation,brain damage,and impaired cognition.Evidence indicates that females are more vulnerable to alcohol-induced damage than males.While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions,their potential to counteract alcohol-induced brain damage remains unclear.In this study,we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice.Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer(^(18)F-FDG)when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice.Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation,cognitive dysfunction,and the conditioned rewarding effects of cocaine.MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration.In addition,mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes(e.g.,Socs3,Tnf,Mtor,and Atf6)in the brains of ethanol-treated female mice.These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation,cognitive dysfunction,and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.
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 a Ph.D.scholarship from the YLSY program of the Republic of Turkiye,Ministry of National Educationfunded by Fight for Sight UK,grant reference#5183/5184。
文摘Glaucoma is characterized by chronic progressive optic nerve damage and retinal ganglion cell death.Although extensive research has been conducted on neuroprotection for retinal ganglion cells,there is still no treatment for clinical use.Recent evidence shows that extracellular vesicles isolated from a variety of stem cells are efficacious in retinal ganglion cell neuroprotection.In this study,we tested the novel extracellular vesicle source of the retinal progenitor R-28 cell line in vitro and in vivo.We isolated and characterized extracellular vesicles from R-28 cells and tested their therapeutic efficacy in terms of retinal ganglion cell survival in vitro and in an in vivo glaucoma model,measuring retinal ganglion cell survival and preservation of their axons.Additionally,we tested extracellular vesicles for their neuroprotective capacity in retinal ganglion cells differentiated from human embryonic stem cells.Finally,we investigated miRNA changes in retinal ganglion cells with R-28 extracellular vesicle treatment,and predicted possible pathways that may be modulated.R-28 extracellular vesicles improved retinal ganglion cell survival but failed to preserve axons significantly.Moreover,the results also illustrated the neuroprotection of R-28 extracellular vesicles on human retinal ganglion cells.Finally,we also showed changes in hsa-miRNA-4443,hsa-miRNA-216a-5p,hsa-let-7e-5p,hsa-miRNA-374b-5p,hsa-miRNA-331-3p,and hsa-miRNA-421 expressions,which may have neuroprotective potential on retinal ganglion cell degeneration.This study will pave the way for miRNA and extracellular vesicle-based neuroprotective therapies for glaucoma.
基金supported by the National Natural Science Foundation of China(82373277).
文摘Delivery carriers serve as a highly efficient approach for precision nutrition and medicine;however,artificial delivery carriers are prone to triggering the immune response and have the disadvantages of poor stability and low bioavailability.Extracellular vesicles(EVs),nucleus-free biological particles composed of phospholipid bilayers secreted by living cells,are a new generation of targeted delivery carriers.In recent years,an increasing number of species have been reported to contain EVs.Among them,food-derived extracellular vesicles(FDEVs)show outstanding comprehensive properties.FDEVs are considered to have great application potential due to their wide range of sources,high yields,absence of human pathogenic pathogens,and ethical concerns.In this review,the preparation,nomenclature,physicochemical characteristics,and preservation methods of FDEVs are discussed,as well as their potential protein markers,bioactivities,and applications as novel targeted delivery carriers of FDEVs from animals,plants,and microorganisms.We also summarized the adverse consequences of FDEVs in current studies,and put forward the problems and challenges in the process of FDEVs research and commercialization.In short,the importance of FDEVs has been highlighted,and FDEVs have good application prospects as a new class of targeted delivery carriers.The current problems should be paid attention to and actively solved.
基金supported by FWO(Fonds voor Wetenschappelijk Onderzoek),grant number G07562NFWO(to BB)。
文摘Neuroinflammation is a key process in the pathogenesis of various neurodegenerative diseases,such as multiple sclerosis(MS),Alzheimer's disease,and traumatic brain injury.Even for disorders historically unrelated to neuroinflammation,such as Alzheimer's disease,it is now shown to precede pathological protein aggregations.
基金supported by the National Natural Science Foundation of China(32330105 and 32301247)National Key R&D Program of China(2023YFD1801100)。
文摘Background An imbalance in the rumen microbiota caused by high-concentrate diets(HCD)is a significant endogenous trigger of mastitis.However,the underlying mechanisms remain largely unknown.Microbial extracellular vesicles(mEVs)are critical mediators of microbe-host communication.However,the role of mEVs in rumen microbiota-mediated mastitis has not yet been reported.In this study,we used an HCD-induced rumen microbiota dysbiosis model to investigate the role of mEVs-derived from rumen microbiota in the pathogenesis of mastitis.Results Our results indicate that HCD leads to mastitis and systemic inflammation.Meanwhile,HCD-fed goats exhibited substantial rumen microbiota dysbiosis and the disruption of the rumen barrier.Transplanting rumen microbiota from HCD goats into mice induced both mastitis and systemic inflammation in the recipients.Specifically,HCD increases the production of mEVs carrying microbial DNA,which can translocate across the compromised rumen barrier to the mammary gland,triggering a mammary inflammatory response via activation of the cGAS-STING-NF-κB/NLRP3 pathway.Furthermore,treating mice with mEVs isolated from the rumen fluid of HCD goats directly induced mastitis,whereas depletion of microbial DNA attenuated mEVs-induced mastitis.Conclusion Our findings suggest that HCD induces rumen microbiota dysbiosis and impairs rumen barrier function.This dysfunction leads to an increase in microbial DNA-containing mEVs,which subsequently leak into the mammary gland.Once there,these mEVs activate the cGAS-STING-NF-κB/NLRP3 signaling pathway,ultimately inducing mastitis.This study provides a new perspective on the“rumen microbiota-mammary gland axis”and enhances the understanding of the pathogenesis of mastitis.
基金supported by the National Natural Science Foundation of China,No.81571211(to FL)the Natural Science Foundation of Shanghai,No.22ZR1476800(to CH)。
文摘Peripheral nerve defect repair is a complex process that involves multiple cell types;perineurial cells play a pivotal role.Hair follicle neural crest stem cells promote perineurial cell proliferation and migration via paracrine signaling;however,their clinical applications are limited by potential risks such as tumorigenesis and xenogeneic immune rejection,which are similar to the risks associated with other stem cell transplantations.The present study therefore focuses on small extracellular vesicles derived from hair follicle neural crest stem cells,which preserve the bioactive properties of the parent cells while avoiding the transplantation-associated risks.In vitro,small extracellular vesicles derived from hair follicle neural crest stem cells significantly enhanced the proliferation,migration,tube formation,and barrier function of perineurial cells,and subsequently upregulated the expression of tight junction proteins.Furthermore,in a rat model of sciatic nerve defects bridged with silicon tubes,treatment with small extracellular vesicles derived from hair follicle neural crest stem cells resulted in higher tight junction protein expression in perineurial cells,thus facilitating neural tissue regeneration.At 10 weeks post-surgery,rats treated with small extracellular vesicles derived from hair follicle neural crest stem cells exhibited improved nerve function recovery and reduced muscle atrophy.Transcriptomic and micro RNA analyses revealed that small extracellular vesicles derived from hair follicle neural crest stem cells deliver mi R-21-5p,which inhibits mothers against decapentaplegic homolog 7 expression,thereby activating the transforming growth factor-β/mothers against decapentaplegic homolog signaling pathway and upregulating hyaluronan synthase 2 expression,and further enhancing tight junction protein expression.Together,our findings indicate that small extracellular vesicles derived from hair follicle neural crest stem cells promote the proliferation,migration,and tight junction protein formation of perineurial cells.These results provide new insights into peripheral nerve regeneration from the perspective of perineurial cells,and present a novel approach for the clinical treatment of peripheral nerve defects.
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 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 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 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Supported by the Ministry of Science and Technology of China,No.2021YFA1101502。
文摘BACKGROUND Extracellular vesicles derived from mesenchymal stromal cells(MSC-EVs)can be used for anti-aging therapy and treating various aging-related diseases.However,the clinical application of MSC-EVs is still limited,mainly due to insufficient in-formation on the preparation process,quality,and mechanism of action of MSC-EVs.To study the biological effects of MSC-EVs in regulating cellular senescence.METHODS In this study,we developed a clinical-grade production process for MSC-EVs and defined the release criteria for products suitable for human use.To support the clinical use of our product as a therapeutic agent,we performed efficacy assays to evaluate the anti-aging capacity of MSC-EVs in vitro and in vivo.RESULTS The functional analysis results revealed that MSC-EVs significantly reduced the levels of senescence-associatedβ-galactosidase,matrix metallopeptidase 1,P21,and interleukin-1βand increased the level of collagen I in a naturally aged cell model of human dermal fibroblasts.Similarly,treatment with MSC-EVs effectively improved D-gal-induced subacute aging in mice,aging-related histopathological changes,oxidative stress,and aging-related gene expression.CONCLUSION These findings indicate that MSC-EVs can partially alleviate D-gal-induced senescence by reducing oxidative stress and regulating metabolism.Overall,these findings strongly suggest that MSC-EVs hold promise for aging therapy.
文摘Cancer is a major global concern due to its high mortality rate.Tumor immunotherapy has revolutionized cancer treatment.However,low response rates and immune-related complications remain challenges.Extracellular vesicles(EVs),including exosomes,have emerged as promising therapeutic tools for various pathological conditions,especially cancer.Evidence indicates that changes in the quantity and composition of EVs can influence the immunosuppressive tumor microenvironment,potentially affecting the effectiveness of immunotherapy.Exploiting EVs for immune sensitization has generated significant clinical interest.This review provides an in-depth understanding of the origin of EVs,their therapeutic applications(such as drug delivery nanoplatforms and cancer immunotherapies,including vaccines),diagnostic potential as tumor biomarkers,ongoing EV-based clinical trials,and the challenges encountered in EV-based cancer immunotherapy.
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.
