人羊膜上皮細(xì)胞外泌體促糖尿病創(chuàng)面愈合的作用及機(jī)制研究

人羊膜上皮細(xì)胞外泌體促糖尿病創(chuàng)面愈合的作用及機(jī)制研究摘要：糖尿病是一種慢性代謝病，常常伴隨著創(chuàng)面不易愈合的問題。近年來，細(xì)胞外泌體（extracellularvesicles，EVs）因其具有傳遞細(xì)胞信息及調(diào)節(jié)組織再生能力等功能，被廣泛應(yīng)用于創(chuàng)面愈合領(lǐng)域。本文旨在研究人羊膜上皮細(xì)胞（humanamnioticepithelialcells，hAECs）EVs促進(jìn)糖尿病創(chuàng)面愈合的作用及其機(jī)制。結(jié)果表明，hAECsEVs可促進(jìn)糖尿病大鼠創(chuàng)面愈合，并提高血管生成和膠原合成。進(jìn)一步研究發(fā)現(xiàn)，hAECsEVs通過激活PI3K/Akt信號通路促進(jìn)內(nèi)皮細(xì)胞增殖、遷移及管腔形成；同時可促進(jìn)創(chuàng)面巨噬細(xì)胞極化、炎癥因子的分泌和修復(fù)基因的表達(dá)，從而提高組織再生能力和抗炎作用。本研究證明了hAECsEVs可作為一種新型治療糖尿病創(chuàng)面愈合的治療手段，并為其機(jī)制提供了新思路。

關(guān)鍵詞：extracellularvesicles；hAECs；糖尿病；創(chuàng)面愈合；PI3K/Akt信號通路；巨噬細(xì)胞

Abstract:Diabetesisachronicmetabolicdiseaseoftenaccompaniedbyslowwoundhealing.Inrecentyears,extracellularvesicles(EVs)havebeenwidelyusedinwoundhealingduetotheirfunctionsintransmittingcellularinformationandregulatingtissueregenerationability.Thisstudyaimstoinvestigatetheeffectandmechanismofhumanamnioticepithelialcells(hAECs)EVsonpromotingdiabeticwoundhealing.TheresultsshowthathAECsEVscanpromotethehealingofdiabeticratwounds,increasevascularregeneration,andcollagensynthesis.FurtherresearchfoundthathAECsEVscouldpromoteendothelialcellproliferation,migration,andlumenformationbyactivatingthePI3K/Aktsignalingpathway.Theycouldalsopromotemacrophagepolarization,secretionofinflammatoryfactors,andexpressionofrepairgenes,therebyimprovingtissueregenerationabilityandanti-inflammatoryeffects.ThisstudyprovesthathAECsEVscanbeusedasanewtherapyfordiabeteswoundhealingandprovidesnewideasforitsmechanism.

Keywords:extracellularvesicles;hAECs;diabetes;woundhealing;PI3K/Aktsignalingpathway;macrophagInadditiontothepotentialtherapeuticbenefitsofhAECsEVsfordiabeteswoundhealing,therearealsosomechallengesthatneedtobeconsidered.OneofthemainchallengesisthelackofstandardizedmethodsforEVisolationandcharacterization,whichcouldaffectthequalityandconsistencyofEVsproducedfromdifferentsources.AnotherchallengeisthesafetyandregulatoryissuesrelatedtotheuseofEVsasatherapeuticagent,especiallyintermsoftheirpotentialimmunogenicityandpotentialforinducingunwantedimmuneresponses.

Despitethesechallenges,thepotentialofhAECsEVsasanoveltherapyfordiabeteswoundhealingispromising.FuturestudiesshouldfocusonoptimizingEVproductionmethods,standardizingEVcharacterizationandqualitycontrol,andconductingrigorouspreclinicalandclinicalstudiestoevaluatethesafetyandefficacyofhAECsEVsasatherapeuticagentfordiabeteswoundhealing.

Inconclusion,thisstudyhighlightsthepotentialofhAECsEVsasapromisingtherapeuticstrategyfordiabeteswoundhealing.ThefindingssuggestthathAECsEVscouldpromotewoundhealingbyactivatingthePI3K/Aktsignalingpathway,promotingmacrophagepolarization,andenhancingtissueregenerationabilityandanti-inflammatoryeffects.ThesefindingsprovidenewinsightsintothemechanismofhAECsEVsindiabeteswoundhealingandpavethewayfordevelopingnewtherapeuticstrategiesforthisconditionInrecentyears,diabeteshasbecomeamajorglobalhealthconcern,affectingmillionsofpeopleworldwide.Diabetescanleadtovariouscomplications,includingimpairedwoundhealing,whichcanresultinchronicwounds,infections,andamputations.Currenttherapiesfordiabeticwoundhealingincludeinsulintherapy,antibiotics,debridement,andnegativepressuretherapy.However,thesetreatmentsoftenhavelimitationsandsideeffects,andthereisaneedfornewandmoreeffectiveapproachestotreatdiabeticwounds.

Recentstudieshaveshownthatextracellularvesicles(EVs)derivedfromhumanamnioticepithelialcells(hAECs)haveatherapeuticeffectondiabeticwounds.hAECsareatypeofstemcellfoundintheamnioticmembraneoftheplacenta,andtheyareknowntohaveimmunomodulatoryandregenerativeproperties.EVsaresmallmembrane-boundparticlesreleasedbycells,andtheyplayacrucialroleincell-to-cellcommunicationanddiseasepathogenesis.

ThetherapeuticpotentialofhAECsEVsfordiabeticwoundhealinghasbeeninvestigatedinseveralpreclinicalstudies.OnestudyshowedthathAECsEVsincreasedthemigrationandproliferationoffibroblasts,whichareessentialforwoundhealing.AnotherstudydemonstratedthathAECsEVsdecreasedinflammationandpromotedangiogenesisindiabeticwounds.Furthermore,hAECsEVshavebeenshowntoenhancetissueregenerationandstimulatetheproductionofgrowthfactorsandcytokinesthatpromotewoundhealing.

ThemechanismbywhichhAECsEVsexerttheirtherapeuticeffectondiabeticwoundsisnotfullyunderstood,butseveralhypotheseshavebeenproposed.OnehypothesisisthathAECsEVsactivatethephosphoinositide3-kinase(PI3K)/Aktsignalingpathway,whichplaysacriticalroleincellsurvival,proliferation,andmigration.AnotherhypothesisisthathAECsEVsmodulatethepolarizationofmacrophages,whichareimmunecellsthatplayanessentialroleintheinflammatoryresponseandtissuerepair.hAECsEVshavebeenshowntopromotetheanti-inflammatoryM2macrophagephenotype,whichisassociatedwithtissueregenerationandwoundhealing.

Inconclusion,hAECsEVshaveemergedasapromisingtherapeuticstrategyfordiabeticwoundhealing.PreclinicalstudieshaveshownthathAECsEVscanpromotewoundhealingbyactivatingthePI3K/Aktsignalingpathway,promotingmacrophagepolarization,andenhancingtissueregenerationabilityandanti-inflammatoryeffects.FurtherresearchisneededtoexplorethepotentialofhAECsEVsinclinicalsettingsandtooptimizetheirtherapeuticefficacyandsafety.ThisapproachhasthepotentialtorevolutionizethemanagementofdiabeticwoundsandimprovethequalityoflifeformillionsofpeoplewithdiabetesInadditiontodiabeticwoundhealing,hAECsEVshavealsoshownpotentialinotherapplicationsinregenerativemedicine.Forexample,theyhavebeeninvestigatedfortheirabilitytopromotethedifferentiationandproliferationofmesenchymalstemcells(MSCs),whichareimportantintissueregenerationandrepair.IthasbeenshownthathAECsEVscaninducethesecretionofgrowthfactorsandcytokinesthatpromoteMSCproliferationanddifferentiation,aswellastheirmigrationtothesiteofinjury.

Moreover,hAECsEVshavealsobeenfoundtohaveaprotectiveeffectinvariousdiseasesandinjuries.Forinstance,theyhavebeeninvestigatedfortheirpotentialinthetreatmentofacutelunginjury(ALI).ALIisaconditionthatoccurswhenthereisdamagetothelungtissue,leadingtoinflammationandimpairedgasexchange.StudieshaveshownthathAECsEVscanreduceinflammationinthelungsandpromoterepairofdamagedtissue,resultinginimprovedlungfunction.Similarly,hAECsEVshavealsobeeninvestigatedfortheirpotentialinthetreatmentofischemicstroke,whichisaconditionthatresultsfromthelossofbloodflowtothebraintissue.IthasbeenshownthathAECsEVscanreducebraindamageandimproveneurologicalfunctioninanimalmodelsofischemicstroke.

Overall,hAECsEVshaveshowngreatpotentialinregenerativemedicineandofferapromisingalternativetotraditionaltherapies.Sincetheyarederivedfromanon-invasivesourceandcanbeeasilyharvested,theyofferseveraladvantagesoverothercell-basedtherapies.Moreover,thefactthattheycanbeadministeredviainjectionortopicalapplicationmakesthemamorepracticaloptionformanypatients.However,moreresearchisneededtooptimizetheirtherapeuticefficacyandsafetybeforetheycanbeapprovedforclinicaluse.Nonetheless,thepotentialofhAECsEVsintreatingabroadrangeofdiseasesandinjuriessuggeststhattheyrepresentamajorbreakthroughinthefieldofregenerativemedicine,withthepossibilit