StemCellSourcesforTreatmentofNeurologicalDiseases(AD,PD,ALS,MS,Stroke,SCI)FabinHan,etal,JournalofNeurorestoratology2015:31–12目前一頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)胎兒神經(jīng)干細(xì)胞治療帕金森氏病臨床研究發(fā)展歷程EvansJR,MasonSL,BarkerRA.ProgBrainRes.2012;200:169-98目前二頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)LindvallO,etal，NatMed.2008May;14(5):501-3THSynucleinOverlayTransplantedfetalmesencephalicdopaminergicneurons(11-16years)developedalpha-synuclein-positiveLewybodiesingraftedneurons目前三頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Synuclein-HostUbiquintin-HostSynuclein-GraftedNeuronsUbiquintin-GraftedNeuronsGraftednigralneuronswerefoundtohaveLewybody-likeinclusions14yearsaftertransplantationintothestriatumofanindividualwithPDOlanowCW.etalNatMed.2008May;14(5):504-6.目前四頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)TransplanteddopamineneuronsinpeoplewithPDdonotcontainLewybodiesMendez,Isacsonetal,,NATUREMEDICINEVOLUME14(5):507-509,2008目前五頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)FreedCR,JNuclMed.2010Jan;51(1):7-15-LongtermStudy-33oftheoriginaltrialparticipantswhowerefollowedfor2yearsaftertransplantationand15ofthesesubjectswhowerefollowedfor2additionalyears.-Theseresultssuggestthatclinicalbenefitandgraftviabilityaresustainedupto4yaftertransplantation.

FreedCR,Neurotherapeutics(2011)8:549–561目前六頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)人體胚胎干細(xì)胞分化的多巴胺神經(jīng)元移植

改善小鼠，大鼠和猴子帕金森氏病的運(yùn)動(dòng)障礙22/29DECEMBER2011|VOL480|NATURE|547，LorenzStuder，etal

MemorialSloan-KetteringCancerCenter目前七頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)ImprovedCellTherapyProtocolforParkinson’sDiseaseBasedonDifferentiationEfficiencyandSafetyofhESC-,HipscandNon-HumanPrimateiPSC-DerivedDANeuronsIsacsonetal,,StemCells.2013;31(8):1548-62.目前八頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)DopaminereleasefromtransplantedneuralstemcellsinParkinsonianratstriatuminvivo.

Zhouz,etal,ProcNatlAcadSciUSA.2014Nov4;111(44):15804-9目前九頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)iPSC-DerivedDopamineNeuronsfunctionafterTransplantationinaNon-HumanPrimateModelofParkinson’sDiseaseCellStemCell.2015Mar5;16(3):269-74.

OleIsacsonetal，HarvardStemCellInstitute目前十頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Stemcell-basedClinicalTrialsfor(ALS)Nuralstem,Inc.thefirstPhaseIclinicaltrialforastemcell-basedtreatmentofALS.Initiatedin2010andcompletedin2013,involvedthetransplan-tationofhumanspinalcord-derivedNSCsintothespinalcordof15latetomid-stageALSpatients目前十一頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Glass,Feldman,E.L.,2012.Lumbarintraspinalinjectionofneuralstemcellsinpatientswithamyotrophiclateralsclerosis:resultsofaphaseItrialin12patients.StemCells30(6),1144–1151.Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87目前十二頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)RESULTS:Unilateralcervical(groupD,n=3)andcervicalplusthoracolumbar(groupE,n=3)microinjectionstotheventralhornhavebeencompletedinambulatorypatients.Onepatientdevelopedapostoperativekyphoticdeformitypromptingcompletionofalaminoplastyinsubsequentpatients.Anotherrequiredreoperationforwounddehiscenceandinfection.Thesolitarypatientwithbulbaramyotrophiclateralsclerosisrequiredperioperativereintubation.CONCLUSION:Deliveryofacellularpayloadtothecervicalorthoracolumbarspinalcordwaswelltoleratedbythespinalcordinthisvulnerablepopulation.Thisencouragingfindingsupportsconsiderationofthisdeliveryapproachforneurodegenerative,oncologic,andtraumaticspinalcordafflictions.IntraspinalstemcelltransplantationinALS:aphaseItrial,2014目前十三頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)iPSCellsWereGeneratedfromPDpatientsandNormalControls目前十四頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)6-OHDA-inducedRatPDModel目前十五頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)HumaniPScellsIntegratedtotheHostBrainof6-OHDA-inducedRatPDModelHanF,WangW,ChenC,DuanJ,etalCytotherapy2015目前十六頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)分化的胎腦神經(jīng)干細(xì)胞移植治療PD目前十七頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)建立大鼠SCI損傷模型A.暴露和部分橫切脊髓外科手術(shù)。B.T7橫斷損傷產(chǎn)生后肢癱瘓。C.無(wú)脊髓損傷的正常大鼠。目前十八頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)RT-PCRtoDetecttheMicroRNAExpressioninRatSCIModelMiR-124MiR-124MiR-124MiR-127MiR-127MiR-127MiR-127MiR-124MiR-133aMiR-133aMiR-133aMiR-181aMiR-181aMiR-181a目前十九頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Real-TimeRT-PCRtoDetecttheMicroRNAExpressioninSCI目前二十頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)干細(xì)胞移植修復(fù)脊髓神經(jīng)損傷目前二十一頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)移植神經(jīng)干細(xì)胞分化的神經(jīng)軸索與宿主脊髓神經(jīng)細(xì)胞及其樹(shù)突形成突觸連接LuPetal，Cell.2012September14;150(6):1264–1273目前二十二頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)BoneMarrowStromalCellIntraspinalTransplantsFailtoImproveMotorOutcomesinaSevereModelof

SCIJournalofNeurotrauma2015，TuszynskiMHTodeterminewhetherlocalmechanismsmediateBMSCneuroprotectiveactionsgraftedallogeneicBMSCstositesofsevere,compressive

spinalcordinjury

(SCI)inSpragueDawleyrats.

Cells

wereadministered48hoursaftertheoriginal

injury.AdditionalanimalsreceivedallogeneicMSCsthatweregeneticallymodifiedtosecreteBDNF,tofurtherdeterminewhetheralocallyadministeredneurotrophicfactorprovidesorextendsneuroprotection.twomonthspost-injury

inaclinicallyrelevantmodelofsevereSCI,BMSCgraftswithorwithoutBDNFsecretionfailedtoimprovemotoroutcomes.Thus,allogeneicgraftsofBMSCsdonotappeartoactthroughlocalmechanisms,andfuture

clinicaltrials

thatacutelydeliverBMSCstoactualsitesof

injury

withindaysareunlikelytobebeneficial.目前二十三頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)IntraspinalStemCellTransplantationinAmyotrophicLateralSclerosis:APhaseISafetyTrial,TechnicalNote,andLumbarSafetyOutcomesNEUROSURGERYVOLUME71|NUMBER2|AUGUST2012DepartmentofNeurosurgery,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,EmoryUniversity,Atlanta,Georgia;DepartmentofNeurology,UniversityofMichigan,AnnArbor,Michigan目前二十四頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)神經(jīng)干細(xì)胞移植方法Eachmicroinjectionseriescomprised5injections(10mL/injection)separatedby4mm.Eachinjection:100000neuralstemcellsderivedfromafetalspinalcord.Twelvepatientsweretreatedwitheitherunilateralorbilateralinjections.Patientsarefollowedclinicallyandradiologicallytoassesspotentialtoxicityoftheprocedure.目前二十五頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)LumbarLaminectomy目前二十六頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Microinjectionplatformapplication目前二十七頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Postoperativeimagingprogression目前二十八頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)Riley,J.,Feldman,E.L.,2014.“IntraspinalstemcelltransplantationinALS:aphaseItrial,cervicalmicroinjectionandfinalsurgicalsafetyoutcomes”.Neurosurgery74(1),77–87

目前二十九頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)ClinicalTrialsusingESCsandiPSCs目前三十頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)ThereisalsoareportofoneJapanesepatientwhoreceivedatransplantofasheetofiPSC-derivedRPE目前三十一頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)SummaryonMolecularMechanismofStemCellTransplantationforNeurologicalDiseasesTransplantedcellssurvive，differentiatetoneurons,astrocytes,oligodendrocyteprecursors(hESC,hiPSC,NSC)andreleaseneurologicaltransmittorssuchasdopamine,Ach.Releaseofneurotrophicfactors(GDNF,GDNE,IGF,)toincreasethefunctionsoftheendogenousneuralstemcellsReleaseofimmuno-regulatoryfactorssuchasIL-2,6,8,10toplayimmuno-modulationandattenuationoftheinflammatoryprocess,suchasMSC.Thetransplantedcellsformedsynapsewithhostcells.OtherssuchasdelayingtheonsetandprolongingsurvivalofSOD1ratsIncreasinghostneurogenesis目前三十二頁(yè)\總數(shù)三十五頁(yè)\編于二十一點(diǎn)今后干細(xì)胞治療神經(jīng)退行性疾病的臨床研究

需要考慮的問(wèn)題1.CellSources：Neuralprojenitors，MSC，hEScells，iPScells2.SCgraftingshouldbeconductedtoensure>100,000dopaminergicneurons（PD）survivepertransplantationsite.3.SCgraftsshouldexhibitr