1、UB-MSC:the new gold standard to treat several human diseases,especially autoimmune diseasesInstitute of Clinical Medicine,Renmin Hospital,Hubei University of MedicineJunming Tang2015.82020/11/31U B-MS C:t h e n e w g o l d s t a n d a r d Outline 一、一、Definition 二、二、Characteristics 三、三、Classification
2、 四、四、Pathogenesis 五、五、Traditional therapy 六、六、Biotherapy(antibody、vaccine、gene therapy)七、七、Cell therapy(DC、HSC、MSC)2020/11/32O u t l i n e 一、D e f i n i t i o n 2 0 2 0/1 1/3 2一、一、Definition Autoimmunity refer to the immune responses to self cells or self components.Autoimmune disease refer to the d
3、isease state resulted from immune responses directed against self cells or self components.2020/11/33一、D e f i n i t i o n A u t o i mmu n i t y r e f e二、二、Characteristics Autoimmune antibody and(or)autoreactive T lymphocyte can be detected.Autoimmune antibody and(or)autoreactive T lymphocyte mediat
4、e immune response which lead to damage or functional disturbanceThe turnover of pathogenetic condition relate with autoimmune response intensityRecurrent attacks and chronic 2020/11/34二、C h a r a c t e r i s t i c s A u t o i mmu n e a三、三、Classification Organ-specific autoimmune disease Graves disea
5、se、insulin-dependent diabetes mellitus Systemic autoimmune disease systemic lupus erythematosus2020/11/35三、C l a s s i f i c a t i o n O r g a n-s p e c i f i c四、四、Pathogenesis Autoimmune antibody Disfunction immunologic system(autoreactive T lymphocyte)Genetics and endocrine2020/11/36四、P a t h o g
6、e n e s i s A u t o i mmu n e a n t i bExamples of Human Autoimmune Diseases with Possible Molecular Mimicry as a Mechanism Clin Rev Allergy Immunol.2012;42(1):102C112020/11/37E x a mp l e s o f H u ma n A u t o i mmu n e D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,RN
7、P,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
8、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 2020/11/38类别病名自身抗原非器官特异性 系统性红斑狼疮胞核成分（D五、五、Traditional therapy General therapy Cortisone Immune inhibitors Others 2020/11/39五、T r a
9、d i t i o n a l t h e r a p y G e n e r a l t六、六、BiotherapyAntibodyVaccinePharmaceutical Biotechnology 2012,19(4):364 368.ChineseJournalofNewDrugs2011,20(8)2020/11/310六、B i o t h e r a p y A n t i b o d y P h a r ma c e u tHow to better solve the suffering of patientsNew ways2020/11/311H o w t o b e
10、 t t e r s o l v e t h e s u f七、七、Gene and Cell therapy DC、NK、CIK、B、T、LAKStem cells(HSC、MSC.）2020/11/312七、G e n e a n d C e l l t h e r a p y D C、N K、C八、八、Stem Cell therapy for AID 1.Definition&Historic landmarks 2.Cell types:MSC origin and 3.Cell harvest,culture and store 4.Delivery method 5.Compar
11、ative Evaluation 6.Animal experimental 7.Mechanism 8.Clinical experimental 9.Conclusion2020/11/313八、S t e m C e l l t h e r a p y f o r A I D 1.D1.Stem cells2020/11/3141.S t e m c e l l s 2 0 2 0/1 1/3 1 415Historic landmarks in the field of stem cell biologyCirc Res.2014;114:21-27.)2020/11/3151 5 H
12、 i s t o r i c l a n d ma r k s i n t h e f i2020/11/3162.C e l l t y p e s 1 6 2 0 2 0/1 1/3 1 6MSC:origin and biological traitsCsar Nombela-Arrieta,Nature Reviews Molecular Cell Biology 12,126-131(2011)SynoviumCartilageDental pulpBone marrow Kidney Pancreas Adipose tissue Muscle Brain liverTonsilP
13、lacenta Umbilical CordThymusPericytesAmniotic fluid2020/11/317MS C:o r i g i n a n d b i o l o g i c a l t r a3.Isolation,culture store of mesenchymal stem cells from Whartons jelly J.Biomedical Science and Engineering,2012,5,580-586 Cryobiology.2014 Jun;68(3):467-72.Current Stem Cell Research&Thera
14、py,2013,8,144-1552020/11/3183.I s o l a t i o n,c u l t u r e s t o r e o f4.Delivery methodsPMID:260680302020/11/3194.D e l i v e r y me t h o d s P MI D:2 6 0 6 8 05.Comparative Evaluation of different MSCsJ Immunol Res.2015:394917.2020/11/3205.C o mp a r a t i v e E v a l u a t i o n o f d iThe a
15、dvantages of UB-MSCsStem Cells International,2013,2461342020/11/321T h e a d v a n t a g e s o f U B-MS C s S t e m Table 1:Phenotypic pro WJ-MSCs compared to MSCs from other sources2020/11/322T a b l e 1:P h e n o t y p i c p r o WJ-MS CTable 2:Transcriptomic pro WJ-MSCs compared to MSCs from other
16、 sources2020/11/323T a b l e 2:T r a n s c r i p t o mi c p r o WJTable 2:Transcriptomic pro WJ-MSCs compared to MSCs from other sources2020/11/324T a b l e 2:T r a n s c r i p t o mi c p r o WJThe differentiation advantages of WJ-MSCs compared to MSCs from other sourcesTissue Eng Part B Rev.2014 Oc
17、t;20(5):523-44.2020/11/325T h e d i f f e r e n t i a t i o n a d v a n t a g e sBetter:autologous/allogenic?Allogenic healthy BM-MSC,UB-MSCCellular Immunology 293(2015)1131212020/11/326B e t t e r:a u t o l o g o u s/a l l o g e n i c?ASummary.1.Umbilical cord derived MSCs are more primitive,prolif
18、erative,regenerative,homing and immuno-suppressive than their adult counterparts2.Healthy UB-MSC is better than MSC from patient-self2020/11/327S u mma r y .1.U mb i l i c a l c o r d d e r6.Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune DiseasesImmune N
19、etwork 2014;14(2):81-882020/11/3286.P r e c l i n i c a l E f f i c a c y a n d Me c7.Mesenchymal stem cell immunosuppression of innate/adaptive immune cellsWorld J Stem Cells 2014;6(5):526-5392020/11/3297.Me s e n c h y ma l s t e m c e l l i mmu n oDifferential toll-like receptor stimulation affec
20、ts mesenchymal stem cell immune-modulation 2020/11/330D i f f e r e n t i a l t o l l-l i k e r e c e p t oSummaryImmunosuppression2020/11/331S u mma r y I mmu n o s u p p r e s s i o n 2 0 2 0/1Permit for application of UB-MSC in human AIDCellStemCell 17,July2,20152020/11/332P e r mi t f o r a p p
21、l i c a t i o n o f U B-8.Clinical trails:Stem cell for AID2020/11/3338.C l i n i c a l t r a i l s:S t e m c e l l fClinical trials(registered as of Aug.8 2015)using HSChaematologica|2010;95(2):184-193.2020/11/334C l i n i c a l t r i a l s (r e g i s t e r e d a sClinical trials(registered)using M
22、SC During HSC transplantationMaria Ester Bernardo,Immunology Letters,Available online 25 June 2015Experimental&Molecular Medicine(2013)45,e22020/11/335C l i n i c a l t r i a l s (r e g i s t e r e d )Clinical trials(registered as of Aug.8 2015)using MSCCellStemCell 17,July2,2015Annu.Rev.Immunol.201
23、3.31:2853162020/11/336C l i n i c a l t r i a l s (r e g i s t e r e d a sClinical trials(registered as of Aug.8 2015)using UB-MSC for AID2020/11/337C l i n i c a l t r i a l s (r e g i s t e r e d a sSafety and feasibilityWoodworthand Furst Arthritis Research&Therapy 2014,16:1132020/11/338S a f e t
24、 y a n d f e a s i b i l i t y Wo o d w o r tRisks and Rewards Stem Cells Dev 2015 Jun.PMID:260680302020/11/339R i s k s a n d R e w a r d s S t e m C e l l s DEffects:CausesEg:Mesenchymal stem cells can induce neuron recovery in multiple sclerosisAmerican Journal of Occupational Therapy,2014,68,273
25、2.Cellular Immunology 293(2015)113121Stem Cell Rev.2012;8(3):940-52.2020/11/340E f f e c t s:C a u s e sE g:Me s e n c h y maSummary:FDA permit for UB-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2020
26、/11/341S u mma r y:F D A p e r mi t f o r U B-MS CTake-home messages UB-MSC:the new gold standard to treat several human diseases,especially autoimmune and neurodegenerative diseases2020/11/342T a k e-h o me me s s a g e s U B-MS C:t h e 1 Tang JM,Luo B,Xiao JH,Lv YX,Li XL,Zhao JH,Zheng F,Zhang L,Ch
27、en L,Yang JY,Guo LY,Wang L,Yan YW,Pan YM,Wang JN,Li DS,Wan Y,Chen SY.VEGF-A promotes cardiac stem cell engraftment and myocardial repair in the infarcted heart.Int J Cardiol.2015;183:221-31.2.Xie WB,Li Z,Shi N,Guo X,Tang J,Ju W,Han J,Liu T,Bottinger EP,Chai Y,Jose PA,Chen SY.Smad2 and myocardin-rela
28、ted transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells.Circ Res.2013;113(8):e76-86.3.Tang JM,Wang JN,Zhang L,Zheng F,Yang JY,Kong X,Guo LY,Chen L,Huang YZ,Wan Y,Chen SY.VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair
29、in the infarcted heart.Cardiovasc Res.2011;91(3):402-11.4.Tang J,Wang J,Yang J,Kong X,Zheng F,Guo L,Zhang L,Huang Y.Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats.Eur J Cardiothorac Surg.2009,36(4):644-50.PMI
30、D:19524448.5.Tang J,Xie Q,Pan G,Wang J,Wang M.Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion.Eur J Cardiothorac Surg.2006;30(2):353-61.6.Tang J,Wang J,Zheng F,Yang J,Kong X,Guo L,Zhang L,Huang Y.Vascular endothelial
31、growth factor promotes cardiac stem cell migration via the PI3K/Akt pathway.Experimental Cell Research.2009,315(20):3521-3531.7.Tang J,Wang J,Kong X,Zheng F,Yang J,Guo L,Zhang L,Huang Y.Mesenchymal stem cells modified with stromal cell-derived factor 1 improve remodeling via paracrine activation of
32、hepatocyte growth factor in a rat model of myocardial infarction.Moleculars and Cells.2010,29(1):1-10.8.Tang J,Wang J,Kong X,Yang J,Zheng F,Guo L,Zhang L,Huang Y.Adenovirus-mediated stromal cell-derived-factor-1 alpha gene transfer improves cardiac structure and function after experimental myocardia
33、l infarction through angiogenic and antifibrotic actions.Molecular Biology Reports.Mol Biol Rep.2010;37(4):1957-69.9.Tang J,Wang J,Zheng F,Kong X,Guo L,Yang J,Zhang L,Huang Y.Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardia
34、c function after acute myocardial infarction in rats.Mol Cell Biochem.2010;339(1-2):107-18.10.Tang JM,Yuan J,Li Q,Wang JN,Kong X,Zheng F,Zhang L,Chen L,Guo LY,Huang YH,Yang JY,Chen SY.Acetylcholine induces mesenchymal stem cell migration via Ca2+/PKC/ERK1/2 signal pathway.J Cell Biochem.2012;113(8):
35、2704-13.11.Zhang L,Dong XW,Wang JN,Tang JM,Yang JY,Guo LY,Zheng F,Kong X,Huang YZ,Chen SY.PEP-1-CAT-transduced mesenchymal stem cells acquire an enhanced viability and promote ischemia-induced angiogenesis.PLoS One.2012;7(12):e525372020/11/343 1 T a n g J M,L u o B,X i a o J H,LPublication 6.Tang J,
36、Wang J,Zheng F,Yang J,Kong X,Guo L,Zhang L,Huang Y.Vascular endothelial growth factor promotes cardiac stem cell migration via the PI3K/Akt pathway.Experimental Cell Research.2009,315(20):3521-3531.7.Tang J,Wang J,Kong X,Zheng F,Yang J,Guo L,Zhang L,Huang Y.Mesenchymal stem cells modified with strom
37、al cell-derived factor 1 improve remodeling via paracrine activation of hepatocyte growth factor in a rat model of myocardial infarction.Moleculars and Cells.2010,29(1):1-10.8.Tang J,Wang J,Kong X,Yang J,Zheng F,Guo L,Zhang L,Huang Y.Adenovirus-mediated stromal cell-derived-factor-1 alpha gene trans
38、fer improves cardiac structure and function after experimental myocardial infarction through angiogenic and antifibrotic actions.Molecular Biology Reports.Mol Biol Rep.2010;37(4):1957-69.9.Tang J,Wang J,Zheng F,Kong X,Guo L,Yang J,Zhang L,Huang Y.Combination of chemokine and angiogenic factor genes
39、and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats.Mol Cell Biochem.2010;339(1-2):107-18.10.Tang JM,Yuan J,Li Q,Wang JN,Kong X,Zheng F,Zhang L,Chen L,Guo LY,Huang YH,Yang JY,Chen SY.Acetylcholine induces mesenchymal stem cell
40、migration via Ca2+/PKC/ERK1/2 signal pathway.J Cell Biochem.2012;113(8):2704-13.11.Zhang L,Dong XW,Wang JN,Tang JM,Yang JY,Guo LY,Zheng F,Kong X,Huang YZ,Chen SY.PEP-1-CAT-transduced mesenchymal stem cells acquire an enhanced viability and promote ischemia-induced angiogenesis.PLoS One.2012;7(12):e525372020/11/344P u b l i c a t i o n 6 .T a n g J,Wa n g J2020/11/3452 0 2 0/1 1/3 4 5
