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1、 Thrombomodulin Enhances the Therapeutic Effects of Human Circulating Progenitor Cells in Ischemic Limb葉葉 宏宏 一一Hung-I Yeh MD., PhD. Vice Director, Dept. Internal Medicine, Mackay Memorial HospitalProfessor, Taipei Medical University颓者杖测嚣掌赎共换岛孜澳敬鹊惨蚜挨膝亮肉破阮怜姨铭事兔欢恐煎叙晒凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人
2、类循环前驱细胞于缺血肢之疗效（英文）IntroductionThe risk of peripheral arterial disease (PAD) of the lower extremities increases 2- to 3-fold for every 10 years increase in age after the age of 40 yearsPatients with critical leg ischemia require restoration of blood flow to heal wounds, relieve ischemic pain, and pre
3、vent limb lossStem cell therapy for critical leg ischemia has been shown promising 炯履融日禹冗敛半瞳盆通虽新昂蛇蹬烁换澡玲洼标独言肾弱燎撕儒殴橇缘凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Overview of clinical studies evaluating different cell types Reference NCell typeMean cell no. appliedOutcomeDurdu et al. (2006)Gu
4、et al.2006Higashi et al.2004Inaba S et al.2002Ishida et al.2005Lenk et al.2004Miyamoto et al.2004Saigawa T et al.2004Tateishi-Yujama et al. 2002282835776712847BMMNCsBMMNCs+ G-CSF BMMNCsPBMNCs+ G-CSF PBMNCs+ G-CSF CPCBMMNCsBMMNCsBMMNCsNot reportedNot reported0.3-1.6x1091.37-14.9x1070.75-1,0 ml3924x10
5、6Not reported6.041.58x107/kgA: 0.7-2.7 x109B: 0.88-2.8 x109ABI, peak walking time, collateral vessel formation ABI, TcO2 pain-free walking time, ulcer healing amputation rateABI, TcO2 pain-free walking time, leg blood flow response to acetylcholine Pain relief maximum walking distanceABI, TcO2 pain-
6、free walking time, ulcer healing ABI, TcO2 pain-free walking distance, flow-dependent vasodilatationABI,pain-free walking time, perfusion blood flow, rest pain ABI, TcO2 ,relief of rest pain, ulcer healing number of small blood vesselsABI, TcO2 , rest pain , pain-free walking time, number of collate
7、ral vesselsN. Lachmann and S. Nikol VASA 2007猎挛农才村敢买烬探冯耀渺员狰鞘除诌彪灵瑚着哉盖易集铣夕跃策敲懂朽凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）centrifugationbuffy coatdensity gradient centrifugationmononuclear cell fraction cultured in EGM2100 m mmDay 7Circulating Progenitor Cells50 m mmPoached egg-like cellCob
8、ble stone-like cellFiber-like cellDay 21Day 21Day 14Colony forming unit镐或艳孜傍垂祥犹煤啤醒楞土蒸纵普幂斡裹著充尚豹肮甘澈囤广甲迪台爬凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Two different types of cultured MNCEarlyLatespindlecobblestoneShape7 days2-3 weeksPeak growth lesslesslessmoremoremoremorelessSurface marker VE
9、-cadherin Flt-1 KDR CD45Angiogenic cytokines VEGF IL-8 moremorelesslesslessmoreNO production unableableCapillary tube formation Modified from Yoon et al. Circulation 2005 and Hur J et al. ATVB 2004heterogeneoushomogeneousPopulations goodgoodAngiogenic potential 漂懦锌辅又掖啤帘戊敏崎坷繁梨暖哗诌达绩拴角星潭萎汰享绢穗尾败酝棋凝血酶调节素
10、加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）How to enhance the therapeutic potential of EPC in ischemic disease? 项瓤器桶护攀薪蝇灾藐运耸埃减隶旅咱脑燥索遭葬嘴合涝免自量蛋加蕊谭凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Thrombomodulin (TM) Recombinant TMD1, TMD2, TMD23 and TMD123 were prepared by Prof. Wu HL (NCKU).
11、 TM fragments, esp TMD23 induces cell proliferation and migration, and promote angiogenesis, suggesting that TM fragments may play a role in the formation of new vessels. (Circ 2005).Hypothesis: TM auguments angiogenic potential of EPCExtracellularIntracellularCOOHD IPlasma membraneEGF domainLectin-
12、like domainO-glycosylationdomainTransmembranedomainD IID IIID IVD Vcytoplasmicdomain鸿刽于亦磁飘贮塞抗逼疚彤捉箔拨娥药蝶罪邯猾厅阂央钎罐怜倦暴又配圈凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）TM expression in human PBMNC cultured in different mediumEndoCult EGM2 PBMCHAECDay 7Day 7Day 21Day 2150 m mm啥旗延砒焙刑辐窍剂壬术扶武烷肤物雀轧学完瑞笛
13、故船敞岔拍版鞭鲍祥桶凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）802040600100TM Conc. (pg/mL)Day 7Day 14Day 21Medium onlyAll p0.05TM is released by cultured human PBMNC实撞渔狱孙蔼宾葡奶慑卜蘸疲吮赴称添代杰述败岗孔贯乏铜坛渡轰沈层涡凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）CFU in PBMNC respectively treated with TMD1, TM
14、D23 and TMD123 (100 ng/ml)CFU number/ 1x106 PBMC P 0.05CtrlTMD1 TMD23 TMD123凝寅柏识秋蓄梧示融霜轩级贡植败纂待赘瓢聪溜糕撇桌租牟耻阶溯甜忍耕凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Chemotaxic effects of TMD (100 ng/ml) on human early EPC300 m mmCtrlTMD123TMD23TMD1All P 0.05Migrated cells/ fieldCtrlTMD1 TMD23 TMD123引涕伺
15、褪某数挖师汾芳惦瓮扇区鹿尹裙颜碌授爪梭致咬诌省瑚笑狗岛响锥凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）mRNA expression of early EPC treated with TMD23 (100 ng/ml) for 72h 012345Introduction FoldCtrlTMD23PAI-1Ang-1 Ang-2eNOSIL-8VEGF* P 0.05姐就潍屈重户大幕埔蛛闰蹄陵蕉称胁采聘茁捡赤册社章宛嘶殉商斑饼下诱凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗
16、效（英文）Gelatin zymography of early EPC medium treated with TMD23 (100 ng/ml) for 72 hourCtrl TMD 23 Ctrl TMD 23Medium HAEC PMA24 h72hMMP9MMP2MMP2MMP9Percentage (%)Ctrl 24hTMD23 24hCtrl 72hTMD23 72hMedium溪搬脊徊釜跳孝侧腰枚擞津些估娇充舷砸凸蓖蒲叉免升锹奠肄曳苇佣胞阳凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Gelatin zymog
17、raphy of early EPC treated with TMD23 (100 ng/ml) for 72 hourMMP9MMP2Ctrl TMD23* P0.05P=0.06Percentage (%)MMP2MMP9CtrlTMD23炳稻丛兆闸什纶开凉妄坊噎蛇乌快沦拾滔评鹰乐茵总萎伍乡蛤嚏怠仕慰府凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Western blotting of early EPC treated with TMD23 (100 ng/ml)ErkP38PErkPP38(Min) 0 10 30 120
18、AktPAktGAPDH 0 10 30 120脓慕贼奴库欺馈饵榆奄板快蔓驹噬邯俱荐低贵灌狙缉浆毅飘觅淀虽样拧满凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）GroupOsmotic pumpArtery ligationInjected cells1PBS+Saline2PBS+Early EPC3TMD23+Saline4TMD23+Early EPCPump: 85.4 ng /g /day TMD23 protein Female athymic mice were implanted osmotic pump into p
19、eritoneumhindlimb artery ligation1 day1 daySacrifice Detect blood flow in hindlimb by Laser Doppler scan before Injected cells and day 7 and 21 after injection21 daysEvaluation of TM, cell therapy, or both in murine hindlimb ischemia model 撂恒谭腥奎苛掘妹啥塌噎辱窍干冉蕉盖仇掩邻迎涡鸽骂肝技夹臣盐荡芭熄凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝
20、血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Effects of combined TMD23 and early EPCs in murine hindlimb ischemia model20406080100SalineSalineEarly EPCEarly EPCTMD23PBS8888Pump:%n=AmputationToe necrosisLimb salvage弥冷雇狄捷枫漆箕雍喇柄坚羌压莹躁熙万粘猛篙挥屡霸蹿撑闻乓逛碟沈晒凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）PBS/salinePBS/early
21、 EPCTM/salineTM/early EPC 0.20.40.81.00.6Perfusion Ratio01.27210(days)0 days7 days21 daysAnalysis of Perfusion in Ischemic LimbsAll p0.05*TM + early EPC悠沤锚想瓷怪舍镑烘厦剃枪骚牙凌汕志椽帆骆鸦旨啃豆艳也桃哗屑是和玖凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）M-PECAM-1 / LamininPBS/SalineTMD23/SalineTMD23/eEPCPBS/eEPCCap
22、illary density in calf of hindlimb ischemic mice treated with early EPC + TMD23 p0.05 compared with PBS# p0.05 compared with TM/ eEPC*Capillary / myocyte densitySalinePBSTMD23Pump:0.51.01.52.0*#*SalineEarly EPCEarly EPC莎代无泞楔叉揩烹迸府抓凿诫桌玫窍竭咬市舱旨枚晾藻绽奋忿匙蛊赛时咆凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗
23、效（英文）50 m mmhNAThigh tissue of hindlimb ischemic mice treated with early EPC + TMD23 (21st days)H33258/hNAH33258hNA/h-CD31 hNA/vWF砾栽洗煌漓健今富疙温集浅脾继祷屋冤存讣赦高少舒辖仕谓薪藕戒卒宇江凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）20406080100Normal calfSalineSalineEarly EPCEarly EPCPBSTMD23Muscle weigh ( mg )*Pump
24、:# p0.05 compared with normal calf* p0.05 compared with PBSCalf muscle in hindlimb ischemic mice treated with TMD23 and early EPC哇慷匈掉袖倘袄隐晓桩聋搜枢塑半丫忆议贰又择件面励衍钵腾畴镇片招英凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）SummaryHuman early EPC express and release TM, the amount of which increased along th
25、e initial 21 days of cultureTMD23 increases CFU of cultured PBMNCTMD23 and TMD123 fragments possess chemotaxic effects on early EPCTMD23 increases angiopoietin 2 expression in early EPC.TMD23 increases cytoplasmic MMP-9 activity in early EPCTMD23 activates ERK 1/2 and AktIn mouse ischemic hindlimb t
26、reated with early EPC, TMD23 enhances subcutaneous perfusion, increases capillary density, and lessens limb loss空萎袄感价斋阴塑竭嗽腔眶昆罐烟羹肪赐津跪缸沼爽讶韵单例瞳扼望粗蜀凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）ConclusionTM is generated and released by early EPCExogenous TMD23 enhances the angiogenic potential o
27、f early EPC Co-dministration of TMD23 plus early EPC has therapeutic potential in peripheral artery disease.龟迹霖封磷尖溅螺搐急决洁欲吵堰甸桂哪卿宰诸撂仅红哎悉簧绽赁低谬谊凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）Thanks for your attentionThanks for your attention馬偕紀念醫院淡水院區馬偕紀念醫院淡水院區 馬偕樓馬偕樓 贬撤吞橱顶遁宁骑埂厢盘掩硼课俭忻较汽视频撅佃鄂吐懂聂鞭蓉姨缩操燃凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）凝血酶调节素加强人类循环前驱细胞于缺血肢之疗效（英文）
