HGF基因修飾的BMSCs條件培養(yǎng)液對(duì)小鼠急性失代償性心力衰竭的保護(hù)作用

HGF基因修飾的BMSCs條件培養(yǎng)液對(duì)小鼠急性失代償性心力衰竭的保護(hù)作用摘要：

目的：研究HGF基因修飾的BMSCs（人骨髓間充質(zhì)干細(xì)胞）條件培養(yǎng)液對(duì)小鼠急性失代償性心力衰竭（AHF）的保護(hù)作用。

方法：采用體外病毒介導(dǎo)的HGF基因修飾、熒光素酶基因標(biāo)記的人骨髓間充質(zhì)干細(xì)胞進(jìn)行條件培養(yǎng)制備HGF-BMSCs-CM（HGF-BMSCs條件培養(yǎng)液），利用小鼠尾靜脈注射方式制備急性失代償性心力衰竭模型。然后通過(guò)分析心肌細(xì)胞形態(tài)結(jié)構(gòu)、心肌膠原沉積及心肌損傷標(biāo)志酶的表達(dá)改變來(lái)評(píng)估HGF-BMSCs-CM對(duì)AHF大鼠心肌保護(hù)的作用。

結(jié)果：HGF-BMSCs-CM治療組與細(xì)胞培養(yǎng)液治療組相比，心肌細(xì)胞形態(tài)結(jié)構(gòu)完整、膠原沉積減少、心肌損傷標(biāo)志酶的表達(dá)降低，提示HGF-BMSCs-CM能夠保護(hù)AHF大鼠心肌。

結(jié)論：通過(guò)HGF基因治療能夠有效地改善心肌細(xì)胞形態(tài)結(jié)構(gòu)、膠原沉積減少、減輕心肌損傷標(biāo)志酶的表達(dá)，從而明顯降低AHF大鼠心肌損傷程度。因此，HGF-BMSCs-CM治療品可作為一種新的治療AHF的策略。

關(guān)鍵詞：HGF基因；BMSCs；條件培養(yǎng)液；急性失代償性心力衰竭；保護(hù)作用

Abstract:

Objective:TostudytheprotectiveeffectofHGFgene-modifiedBMSCs(humanbonemarrowmesenchymalstemcells)conditionedmediumonacutedecompensatedheartfailure(ADHF)inmice.

Methods:HGFgene-modifiedandluciferasegene-labeledhumanbonemarrowmesenchymalstemcellswerepreparedbyvirus-mediatedgenemodificationinvitroandconditionedmediumwaspreparedtoprepareHGF-BMSCs-CM.Acutedecompensatedheartfailuremodelwaspreparedbyintravenousinjectioninmice.Then,thechangeofmyocardialcellmorphology,collagendepositionandtheexpressionofmyocardialinjurymarkerswereanalyzedtoevaluatetheeffectofHGF-BMSCs-CMonmyocardialprotectioninADHFrats.

Results:Comparedwiththecellculturemediumtreatmentgroup,theHGF-BMSCs-CMtreatmentgrouphadintactmyocardialcellmorphology,reducedcollagendeposition,anddecreasedexpressionofmyocardialinjurymarkers,indicatingthatHGF-BMSCs-CMcanprotectthemyocardiumofADHFrats.

Conclusion:HGFgenetherapycaneffectivelyimprovemyocardialcellmorphology,reducecollagendeposition,andreducetheexpressionofmyocardialinjurymarkers,therebysignificantlyreducingthedegreeofmyocardialinjuryinADHFrats.Therefore,HGF-BMSCs-CMcanbeusedasanewstrategyforthetreatmentofADHF.

Keywords:HGFgene;BMSCs;conditionedmedium;acutedecompensatedheartfailure;protectiveeffecAcutedecompensatedheartfailure(ADHF)isaseriousconditionthatcanleadtosignificantmorbidityandmortality.CurrenttreatmentoptionsforADHFarelimited,andthereisaneedfornewtherapiesthatcaneffectivelyprotectthemyocardiumandimprovepatientoutcomes.Inthisstudy,weexploredthepotentialofhepatocytegrowthfactor(HGF)genetherapyasanovelapproachfortreatingADHF.

OurresultsindicatethatHGFgenetherapycansignificantlyimprovemyocardialcellmorphologyinADHFrats.Specifically,weobservedareductioninmyocardialcellswellinganddisorganization,aswellasadecreaseincollagendeposition.ThesefindingssuggestthatHGFgenetherapymaybeeffectiveinpromotingmyocardialrepairandregenerationinADHF.

Furthermore,wefoundthatHGFgenetherapycanreducetheexpressionofmyocardialinjurymarkersinADHFrats,includingCK-MBandLDH.ThissuggeststhatHGFgenetherapymaybeeffectiveinprotectingthemyocardiumfrominjuryandpreventingfurtherdamageinADHF.

Inaddition,weevaluatedthepotentialofHGF-BMSCs-CMasanewtherapyforADHF.OurresultsindicatethatHGF-BMSCs-CMcaneffectivelyprotectthemyocardiumofADHFrats.Specifically,weobservedareductionincollagendepositionandanimprovementinmyocardialcellmorphology.ThesefindingssuggestthatHGF-BMSCs-CMmaybeeffectiveinpromotingmyocardialrepairandregenerationinADHF.

Overall,ourfindingssuggestthatHGFgenetherapyandHGF-BMSCs-CMmaybepromisingnewstrategiesforthetreatmentofADHF.Furtherresearchisneededtodeterminethesafetyandefficacyofthesetherapiesinhumans,butthesefindingsprovideastrongfoundationforcontinuedinvestigationinthisareaInadditiontothepotentialuseofHGFgenetherapyandHGF-BMSCs-CMinthetreatmentofADHF,thereareseveralothertherapiesthathaveshownpromiseinpreclinicalandclinicalstudies.

Onepromisingapproachistheuseofstemcelltherapy.Mesenchymalstemcells(MSCs)havebeenshowntohavetheabilitytodifferentiateintocardiaccellsandstimulatetheregenerationofdamagedmyocardium.MSCshavealsobeenshowntosecretefactorsthatpromoteangiogenesisandanti-inflammatoryeffects.

Clinicaltrialsusingbonemarrow-derivedMSCshaveshownpromisingresultsinimprovingheartfunctionandreducingmortalityinpatientswithADHF.However,thereisstillaneedforfurtherresearchtodeterminetheoptimaldoseanddeliverymethodofMSCsandtodetermineanypotentialsafetyconcerns.

AnotherpotentialtherapyforADHFistheuseofcardiacregenerativepatches.Thesepatchesconsistofascaffoldmaterialthatisimplantedontothesurfaceoftheheartandisseededwithcardiaccellsorstemcells.Thescaffoldprovidesasupportiveenvironmentforthecellstogrowanddifferentiateintofunctionalcardiactissue.

Preclinicalstudieshaveshownthatcardiacregenerativepatchescanimprovecardiacfunctionandreducescarformationinanimalmodelsofheartfailure.Clinicaltrialsarecurrentlyongoingtodeterminethesafetyandefficacyofthesepatchesinhumans.

Inconclusion,whileADHFremainsasignificantclinicalchallenge,therearemultiplepromisingtherapiesthatarecurrentlybeingexplored.HGFgenetherapyandHGF-BMSCs-CMhaveshownpotentialinpreclinicalstudies,andfurtherresearchisneededtoevaluatetheirsafetyandefficacyinhumans.Additionally,stemcelltherapyandcardiacregenerativepatchesareotherpromisingapproachesthatholdgreatpotentialforthetreatmentofADHF.Withcontinuedresearchanddevelopment,itishopedthatthesetherapieswillultimatelyprovidepatientswithbetteroutcomesandimprovedqualityoflifeDespitesignificantadvancementsinthemanagementofheartfailure,acutedecompensatedheartfailure(ADHF)remainsasignificantchallengethatisassociatedwithhighmorbidityandmortalityrates.TraditionalpharmacologicalandmechanicaltherapieshavealimitedimpactontheunderlyingmechanismsofADHF,thuspromptingtheexplorationofnoveltherapeuticapproachesthattargetthepathophysiologyofthedisease.Amongtheseapproaches,genetherapy,stemcelltherapy,andcardiacregenerativepatcheshaveemergedaspromisingstrategiesforthetreatmentofADHF.

Genetherapyinvolvesthedeliveryofgenesthatencodefortherapeuticproteinsorpeptidestotargettissues.Hepatocytegrowthfactor(HGF)isapotentmitogenandinitiatorofcellularmigration,proliferation,andsurvival.Inpreclinicalstudies,HGFgenetherapyhasbeenshowntostimulatecardiomyocyteproliferation,angiogenesis,andreducecardiacfibrosis,resultinginimprovedcardiacfunctioninanimalmodelsofheartfailure(1).However,thesafetyandfeasibilityofHGFgenetherapyinhumansremaintobeevaluated.

Anotherpromisingapproachistheuseofconditionedmediaobtainedfrombonemarrow-derivedmesenchymalstemcells(BMSCs-CM)thatsecreteavarietyofgrowthfactors,cytokines,andextracellularvesiclesthathaveimmunomodulatoryandanti-inflammatoryeffects.InananimalmodelofADHF,administrationofBMSCs-CMsignificantlyimprovedcardiacfunctionandreducedpathologicalremodeling(2).However,thespecificmechanismsthroughwhichBMSCs-CMexerttheirtherapeuticeffectsrequirefurtherinvestigation.

Stemcelltherapyinvolvesthetransplantationofstemcells,suchasBMSCs,cardiacprogenitorcells,orinducedpluripotentstemcells,intothedamagedmyocardiumtoregeneratefunctionalcardiomyocytesorpromotetissuerepair.Inpreclinicalstudies,stemcelltherapyhasshownpromisingresultsinimprovingcardiacfunctionandreducingmortalityratesinanimalmodelsofheartfailure(3).However,theoptimalsource,dosage,anddeliverymethodofstemcellsremaintobedetermined,andthesafetyandefficacyofstemcelltherapyinhumanshavenotyetbeenfullyestablished.

Cardiacregenerativepatchesarebiomaterial-basedscaffoldsthatcanbeimplantedontothedamagedmyocardiumtoprovidemechanicalandstructuralsupportandpromotetissueregeneration.Thesepatchescanbecomposedofnaturalorsyntheticmaterialsandcanbeseededwithstemcellsorgrowthfactorstoenhancetheirregenerativeproperties.Inpreclinicalstudies,cardiacpatcheshavebeenshowntopromotecardiomyocyteproliferation,angiogenesis,andremuscularizationoftheinfarctedmyocardium,leadingtoimprovedcardiacfunc