干細(xì)胞修復(fù)受損的心臟

StemCellRepairtheInjuredHeartInstituteofClinicalMedicine,RenminHospital,HubeiUniversityofMedicineJUN-MINGTANG2014.10Afour-chamberpump

InitiatingpowerforbloodcirculationPushingthebloodflowthroughanestimated60,000milesofbloodvesselsHeartpumpsover1milliongallonsperyearCardiologyThestudyofthenormalheartandassociateddiseasesisknownascardiologyTheHeartSituatedbetweenthelungsinthemediastinumTwo-thirdsofitsmasstotheleftofthemidline.TworigidstructuralcoverThevertebralcolumnThesternumExternalcompressiononthechestcanbeusedtoforcebloodoutoftheheartandintothe circulation(CPRorcardiopulmonaryresuscitation)

LocationoftheHeartWrappedinasacLikeputtingyourfeastintoaballoonVisceralpericardiumParietalpericardiumPericardialcavity(containpericardialfluid)AnatomyoftheHeart(I)AnatomyoftheHeart(II)Chambersandsulci(sulcus)Fourchambers2upperatria2lowerventriclesSulci:GroovesonsurfaceofheartcontainingcoronarybloodvesselsandfatCoronarysulcusEncirclesheartandmarkstheboundarybetweentheatriaandtheventriclesAnteriorinterventricularsulcusMarkstheboundarybetweentheventriclesanteriorlyPosteriorinterventricularsulcusMarkstheboundarybetweentheventriclesposteriorlyElectrocardiogram(ECG)Indirectlyrecordstheelectricalactivityoftheheart.Measuredwithbody-surfaceelectrodesAmplifyingthetinyelectricalchangesontheskinReflectstheactionofthecardiacmuscleasitdepolarizesandrepolarizesRepresentstemporalandspatialsummationofAPsofthemyocardialfibers.Electrodes,amplificationandappropriatedisplayarerequired.Myocardiumischemia/infarction7TypicalSymptom8precordialpainTypicalinspection---ECG9Cardiacbiomarkers10Thereareanumberofdifferentbiomarkers,troponinsareconsideredtobethebestandrelianceonoldertests(suchasCreatinekinaseMB,CK-MB)ormyoglobinisdiscouraged.CopeptinmaybeusefultoruleoutMIrapidlywhenusedalongwithtroponin.Typicalinspection-ECho11JTehranHeartCent.Jan2013;8(1):1–13.TheRoleofEchocardiographyinCoronaryArteryDiseaseandAcuteMyocardialInfarctionTypicalinspection---Coronarystenosesoncineangiogramandintravascularultrasound.12ExerciseSPECT99mTcsestamibiscanina64-year-oldmalepatientwithapreviousinfarctTreatmentstrategies141.Generaltreatment2.Restrictandreduceinfarctionarea1).Drugtherapy:

nitroglycerin;β-blockers;Calciumchannelblockers2).Thrombolytictherapy3).Percutaneoustransluminalangioplasty(PTCA)4).surgicalbypassoperationorhearttransplantationPROBLEM15AboveTtreatmentNOSavedeadcardiomyocytesLittleHowtoresolvetheclinicalproblem?Earlyexplorationstudy↙TransplantationofembryoniccellsforbetterintegrationwithhostmyocardialcellsMIEmbryonic,fetal,neonatalratorpigmyocardialcells,smoothmusclecells,adultorfetalcardiomyocytes,AT-1atrialcells17FundamentalResearchStemcellresearch:newwayforlife!18HematopoieticandMesenchymalStemCells1920HSCdifferentiationintocardocytes.21HSCdidnotdifferentiationintocardocytes?

HaematopoieticstemcellsdonottransdifferentiateintocardiacmyocytesinmyocardialinfarctsNature428,664-668(8April2004)However,heartfunctionwasimproved.Why?2223MSCMOBLIZATIONANDDIFFERENTIATIONFigure4.2EvidenceofmobilizationanddifferentiationofBMMSCintocardiomyocytes.GFP-markedMSCs(CMGcell)weretransplantedintotheintratibialbonemarrowspace(A).ThetransplantedCMGcellsdifferentiatedintoadipocytes(B),osteoblasts(C),andsomeremainedasMSCs(D).EGFPwasstainedbrownwithimmunohistochemistry.Therecombinantplasmid-containingEGFPdrivenbyanMLC-2vpromoterwasstablytransfectedintoMSCs(E).ThecellsexpressedEGFPupondifferentiationintocardiomyocytes.Theintra-bonemarrow-bonemarrowtransplantationwasperformedfollowedbyinductionofmyocardialinfarctionandadministrationofG-CSF.EGFP+cardiomyocyteswereobservedintheinfarctedandborderzoneareas(FandG).IBM-BMT=intra-bonemarrow–bonemarrowtransplantation;CMG=cardiomyogenic2425G-CSFforheartdiseasetherapy26CardiacstemcellsLocationMarkers：c-Kit、Sca、MDR、Flk-1、IGFR1PhysiolRev.2005Oct;85(4):1373-416.27MSCactivateCSCmigrationinvivoCardiovascRes.2011;91(3):402-11.TheimprovementofinfarctedheartfunctionaftertransplantationofcardiactissuesheetsbioengineeredwithmouseEScell-deriveddefinedcardiaccellpopulations28TheadvantagesofPSCsforcardiacregeneration2930PotentialmechanismsofbenefitofbonemarrowderivedcellsaftermyocardialinfarctionTransdifferentiationtocardiomyocytesAttenuationofRemodellingArteriogenesisorAngiogenesisParacrineeffectsCellfusionReductionofapoptosisPromotingendogenousCardiacstemcellfunction31ClinicalResearchClinicaldevelopmentofnoveltherapies32StemCellClinicalTrials

/FDA:STEMCELLSTRIALS34Chestpain+STEMIStenting+UsualmedicalRxDay1-9BonemarrowharvestAssessments:SafetyFunctionalClassHoltermonitoringTreadmillCardiacfunction:MRI,EchoPerfusion:SPECT,MRIIntracoronarycellproductinfusionDays1-10cellproductScreeningEchoEF<50%SPECTMRIIntracoronarybonemarrowmononuclearcellinjectionafteracuteSTelevationMICellproductconcentration一、Cellharvestandtransplantation36二、Deliveryoptionsforstemcells

IntracoronaryCoronaryArteryInfusionDirectInjectionintheVentricularWallIntravenousInfusionBonemarrowmobilizationTransendocardialInjectionTransepicardialInjectionTranscoronaryVeinInjectionDeliverydevicesDirectaccesstotheleftventricleforcellimplantationinsmallanimal38Minimallyinvasiveleftthoracotomy;directaccesstotheleftventricleforcellimplantation39Video-assistedthoracoscopicsurgicalapproachforcellimplantationtherapy40ThedaVincisystemcomponents41三、Transplantedcells:FateandFunction42ImagingiscrucialforinvivotrackingofcellsandbetterunderstandingandevaluationoftheeffectsofcelltherapyCellTrackingbyUseofinvasiveImaging43EXPERIMENTALCELLRESEARCH315(2009)3521–353Brdu,DAPI,Hoechst33342,PKH26,GFP,β－galaetosidase(β-Gal),Y-chromosomeCellTrackingbyUseofNoninvasiveImaging44Restingperfusion:SPECTtotalseverityscoreRestingtotalseverityscoreControl,5millioncells=+1310,15millioncells=-256(p=0.01)BonemarrowCD34+cellinjectionafterSTEMI(AMRS1)46Summary:TechniquesforInVivoImagingofLabeledTransplantedCells47Circulation.2006;114:339-35249CellTherapyTrialsinPatientsWithdifferentpatternofdiseaseHumanstudieswithcelltherapyincardiovasculardiseasesCelltypes:

Endothelialprogenitorcells:Bonemarrowmononuclearcells,Bonemarrowendothelialprogenitorseg.CD34+,CD133+etcPeripheralbloodprogenitors(exvivoexpansion)CordbloodSkeletalmyoblastsMesenchymalstemcellsResidentcardiacstemcellsAdiposetissueprogenitorsDiseasestates:

AcuteMI,Heartfailurewithscarorhibernatingmyocardium,Chronicischemianotamenabletoconventionalrevascularization四、celltypes5152五、SafetyAnalysis

53六、Problem

1.aging2.lowsurvivalrate3.lowengrafmentefficience4.lowdifferentiationefficience5lowhoming,retentionrate6Arrhythmias7.restenosis8.calcification9.abnormalcelldifferentiation54StrategiestoAugmentHoming,Survival,

andEngraftmentTargetingAdhesionMolecules:IntegrinsandSelectins.eg:HMGB-1EnhancingChemokine/Cytokine/GrowthFactorSignaling.eg:SDF-1/CXCR4,VEGF/VEGFRKinases.eg:Akt,glycogensynthasekinase,andintegrin-linkedkinaseEnhancingCardiacRegeneration55Table1.Cytokine,GrowthFactors,andCell-to-CellCommunicationPathwaysInvolvedinCardiacDifferentiation56Table2.