UB-MSC: the new gold standard to treat several human diseases, especially autoimmune diseasesInstituteofClinicalMedicine,RenminHospital,HubeiUniversityofMedicineJunmingTang2015.8Outline一、一、Definition二、二、Characteristics三、三、Classification四、四、Pathogenesis五、五、Traditionaltherapy六、六、Biotherapy(antibody、vaccine、genetherapy)七、七、Celltherapy(DC、HSC、MSC)一、一、DefinitionAutoimmunity refer to the immune responses to self cells or self components.Autoimmune disease refer to the disease state resulted from immune responses directed against self cells or self components. 二、二、CharacteristicsAutoimmune antibody and (or) autoreactive T lymphocyte can be detected.Autoimmune antibody and (or) autoreactive T lymphocyte mediate immune response which lead to damage or functional disturbanceThe turnover of pathogenetic condition relate with autoimmune response intensityRecurrent attacks and chronic 三、三、ClassificationOrgan-specific autoimmune disease Graves disease、insulin-dependent diabetes mellitusSystemic autoimmune disease systemic lupus erythematosus四、四、PathogenesisAutoimmune antibodyDisfunction immunologic system(autoreactive T lymphocyte)Genetics and endocrineExamplesofHumanAutoimmuneDiseaseswithPossibleMolecularMimicryasaMechanismClinRevAllergyImmunol.2012;42(1):102C11类别类别病名病名自身抗原自身抗原非器官特异性非器官特异性系统性红斑狼疮系统性红斑狼疮胞核成分（胞核成分（DNA,DNP,RNP,SmDNA,DNP,RNP,Sm）类风湿性关节炎类风湿性关节炎变性变性IgG,IgG,类风湿相关的核抗原类风湿相关的核抗原干燥综合征干燥综合征细胞核（细胞核（SS-A,SS-BSS-A,SS-B）, ,唾液腺管唾液腺管胞浆线粒体胞浆线粒体, ,微粒体微粒体, ,红细胞红细胞, ,血小板血小板混合性结缔组织病混合性结缔组织病细胞核（细胞核（RNPRNP）器官特异性器官特异性乔本甲状腺炎乔本甲状腺炎甲状腺球蛋白、微粒体甲状腺球蛋白、微粒体GravesGraves病病甲状腺细胞表面甲状腺细胞表面THSTHS受体受体AddisonAddison病病肾上腺皮质细胞肾上腺皮质细胞幼年型糖尿病幼年型糖尿病胰岛细胞胰岛细胞萎缩性胃炎萎缩性胃炎胃壁细胞胃壁细胞溃疡性结肠炎溃疡性结肠炎结肠上皮细胞结肠上皮细胞原发性胆汁性肝硬化原发性胆汁性肝硬化胆小管细胞、线粒体胆小管细胞、线粒体重症肌无力重症肌无力乙酰胆碱受体乙酰胆碱受体自身免疫性溶血性贫血自身免疫性溶血性贫血红细胞红细胞特发性血小板减少性紫癜特发性血小板减少性紫癜血小板血小板常见自身免疫病常见自身免疫病 五、五、TraditionaltherapyGeneraltherapyCortisoneImmuneinhibitorsOthers六、六、BiotherapyAntibodyVaccinePharmaceuticalBiotechnology2012,19(4):364368.ChineseJournalofNewDrugs2011,20(8)Howtobettersolve the suffering of patientsNew ways七、七、GeneandCelltherapyDC、NK、CIK、B、T、LAKStemcells(HSC、MSC.）八、八、StemCelltherapyforAID1.Definition & Historic landmarks 2.Cell types: MSC origin and 3.Cell harvest, culture and store4.Delivery method5.Comparative Evaluation6.Animal experimental7.Mechanism8. Clinical experimental 9.Conclusion1.Stemcells15Historic landmarks in the field of stem cell biologyCirc Res. 2014;114:21-27.)2.Celltypes1616MSC:originandbiologicaltraitshttp:/discovery.lifemapsc.com/library/images/in-vivo-mesenchymal-stem-cells-originCsarNombela-Arrieta,NatureReviewsMolecularCellBiology12,126-131(2011)SynoviumCartilageDental pulpBone marrow Kidney Pancreas Adipose tissue Muscle Brain liverTonsilPlacentaUmbilical Cord ThymusPericytes Amniotic fluid3.Isolation, culture store of mesenchymal stem cells from Whartons jellyJ.BiomedicalScienceandEngineering,2012,5,580-586Cryobiology.2014Jun;68(3):467-72.Current Stem Cell Research & Therapy, 2013, 8, 144-1554.DeliverymethodsPMID:260680305.ComparativeEvaluationofdifferentMSCsJImmunolRes.2015:394917.TheadvantagesofUB-MSCsStemCellsInternational,2013,246134Table1:PhenotypicprofileofWJ-MSCscomparedtoMSCsfromothersourcesTable2:TranscriptomicprofileofWJ-MSCscomparedtoMSCsfromothersourcesTable2:TranscriptomicprofileofWJ-MSCscomparedtoMSCsfromothersourcesThedifferentiationadvantagesofWJ-MSCscomparedtoMSCsfromothersourcesTissue Eng Part B Rev. 2014 Oct;20(5):523-44. Better:autologous/allogenic?Allogenic healthy BM-MSC, UB-MSCCellularImmunology293(2015)113121Summary.1.Umbilical cord derived MSCs are more primitive, proliferative, regenerative, homing and immuno-suppressive than their adult counterparts2.Healthy UB-MSC is better than MSC from patient-self6.Preclinical Efficacy and Mechanisms of MesenchymalStemCellsinAnimalModelsofAutoimmuneDiseasesImmune Network 2014;14(2):81-887.Mesenchymalstemcellimmunosuppressionofinnate/adaptiveimmunecellsWorldJStemCells2014;6(5):526-539Differentialtoll-likereceptorstimulationaffectsmesenchymalstemcellimmune-modulationSummaryImmunosuppressionPermitforapplicationofUB-MSCinhumanAIDCellStemCell17,July2,20158.Clinicaltrails:StemcellforAIDClinical trials (registered as of Aug.8 2015 ) using HSChaematologica|2010;95(2):184-193.Clinical trials (registered ) using MSC During HSC transplantationMariaEsterBernardo,ImmunologyLetters,Availableonline25June2015Experimental&MolecularMedicine(2013)45,e2Clinical trials (registered as of Aug.8 2015 ) using MSCCellStemCell17,July2,2015Annu.Rev.Immunol.2013.31:285316Clinical trials (registered as of Aug.8 2015 ) using UB-MSC for AIDSafetyandfeasibilityWoodworthandFurstArthritisResearch&Therapy2014,16:113RisksandRewardsStemCellsDev2015Jun.PMID:26068030Effects:CausesEg:MesenchymalstemcellscaninduceneuronrecoveryinmultiplesclerosisAmericanJournalofOccupationalTherapy,2014,68,2732.CellularImmunology293(2015)113121StemCellRev.2012;8(3):940-52.Summary:FDApermitforUB-MSC多系统硬化多系统硬化风湿性关节炎风湿性关节炎I型糖尿病型糖尿病系统性红斑狼疮系统性红斑狼疮狼疮肾炎狼疮肾炎肝夏科氏肝硬变肝夏科氏肝硬变自身免疫性肝炎自身免疫性肝炎IgA肾病肾病克隆病克隆病色素性视网膜炎色素性视网膜炎血栓闭塞性脉管炎血栓闭塞性脉管炎进行性面部偏侧萎缩进行性面部偏侧萎缩Take-homemessagesUB-MSC: the new gold standard to treat several human diseases, especially autoimmune and neurodegenerative diseases431TangJM,LuoB,XiaoJH,LvYX,LiXL,ZhaoJH,ZhengF,ZhangL,ChenL,YangJY,GuoLY,WangL,YanYW,PanYM,WangJN,LiDS,WanY,ChenSY.VEGF-Apromotescardiacstemcellengraftmentandmyocardialrepairintheinfarctedheart.IntJCardiol.2015;183:221-31.2.XieWB,LiZ,ShiN,GuoX,TangJ,JuW,HanJ,LiuT,BottingerEP,ChaiY,JosePA,ChenSY.Smad2andmyocardin-relatedtranscriptionfactorBcooperativelyregulatevascularsmoothmuscledifferentiationfromneuralcrestcells.CircRes.2013;113(8):e76-86.3.TangJM,WangJN,ZhangL,ZhengF,YangJY,KongX,GuoLY,ChenL,HuangYZ,WanY,ChenSY.VEGF/SDF-1promotescardiacstemcellmobilizationandmyocardialrepairintheinfarctedheart.CardiovascRes.2011;91(3):402-11.4.TangJ,WangJ,YangJ,KongX,ZhengF,GuoL,ZhangL,HuangY.Mesenchymalstemcellsover-expressingSDF-1promoteangiogenesisandimproveheartfunctioninexperimentalmyocardialinfarctioninrats.EurJCardiothoracSurg.2009,36(4):644-50.PMID:19524448.5.TangJ,XieQ,PanG,WangJ,WangM.Mesenchymalstemcellsparticipateinangiogenesisandimproveheartfunctioninratmodelofmyocardialischemiawithreperfusion.EurJCardiothoracSurg.2006;30(2):353-61.6.TangJ,WangJ,ZhengF,YangJ,KongX,GuoL,ZhangL,HuangY.VascularendothelialgrowthfactorpromotescardiacstemcellmigrationviathePI3K/Aktpathway.ExperimentalCellResearch.2009,315(20):3521-3531.7.TangJ,WangJ,KongX,ZhengF,YangJ,GuoL,ZhangL,HuangY.Mesenchymalstemcellsmodifiedwithstromalcell-derivedfactor1improveremodelingviaparacrineactivationofhepatocytegrowthfactorinaratmodelofmyocardialinfarction.MolecularsandCells.2010,29(1):1-10.8.TangJ,WangJ,KongX,YangJ,ZhengF,GuoL,ZhangL,HuangY.Adenovirus-mediatedstromalcell-derived-factor-1alphagenetransferimprovescardiacstructureandfunctionafterexperimentalmyocardialinfarctionthroughangiogenicandantifibroticactions.MolecularBiologyReports.MolBiolRep.2010;37(4):1957-69.9.TangJ,WangJ,ZhengF,KongX,GuoL,YangJ,ZhangL,HuangY.Combinationofchemokineandangiogenicfactorgenesandmesenchymalstemcellscouldenhanceangiogenesisandimprovecardiacfunctionafteracutemyocardialinfarctioninrats.MolCellBiochem.2010;339(1-2):107-18.10.TangJM,YuanJ,LiQ,WangJN,KongX,ZhengF,ZhangL,ChenL,GuoLY,HuangYH,YangJY,ChenSY.AcetylcholineinducesmesenchymalstemcellmigrationviaCa2+/PKC/ERK1/2signalpathway.JCellBiochem.2012;113(8):2704-13.11.ZhangL,DongXW,WangJN,TangJM,YangJY,GuoLY,ZhengF,KongX,HuangYZ,ChenSY.PEP-1-CAT-transducedmesenchymalstemcellsacquireanenhancedviabilityandpromoteischemia-inducedangiogenesis.PLoSOne.2012;7(12):e52537Publication 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