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1、In Vivo Cellular and Molecular MRI of Embryonic Stem Cell Survival and Proliferation,Phillip C. Yang, MD Assistant Professor Division of Cardiovascular Medicine Stanford University (No disclosure or conflict of interest) GREAT WALL INTERNATIONAL CONGRESS OF CARDIOLOGY BEIJING, CHINA 2008,I. Stem Cel
2、l Therapy: Congestive Heart Failure,Coronary artery disease: #1 killer in the United States 1.1 million new or recurrent MI and 500,000 deaths per year Improved acute MI therapy shift in the landscape Congestive heart failure: #1 cause of hospital admissions in the US Prevalence: 5 million patients
3、Incidence: 300,000 patients/year Advanced therapy: 5-year survival 50% Heart transplant: 1,000 pt/year Recent stem cell research: alternative therapeutic option?,II. Evaluation of Cell Therapy,Clinical trials: modest, temporary improvement in LVEF Cell survival following transplantation into the hea
4、rt Fundamental biology of cell therapy: Restore & regenerate In vivo imaging of stem cell viability,III. In Vivo Multi-Modality Imaging,(Hendry et al, JCTS, 2008),In vivo molecular and cellular MRI,Protein,Reporter Gene,Iron-oxide labeld MAb,mRNA,Iron-oxide,HA,myc,Manganese,Ca2+-channel,IV. Cellular
5、 MRI: iron-oxide,H&E,Prus blue,H&E 40x,P blue 40x,(Hung et al, Circulation: Cardiovascular Img. 2008),(Suzuki et al, MRM, 2007),Metabolic effects: 3 transfection methods,In vivo MRI of myocardial restoration,End-diastole,End-systole,MI control,Non-treated heart,Treated heart,(Hendry et al, JCTS 2008
6、),mESC,mESC,Fibroblast,Cellular survival,(Cunningham et al, Magn Reson Med 2005),Survival,d2,d5,d15,d2,d5,d7,GRE,OR,In vivo serial survival and proliferation,1POD,4POD,7POD,10POD,16POD,4,5,6,(Suzuki et al, MRM, accepted, 2008),Control,0.01,0.05,0.10,0.50,1.00,(mM),p/sec/cm2/sr,V. Cellular MRI: Manga
7、nese,3.00,0.01 with Dead cells,(Yamada et al, MRM, submitted),Biological modulation of Ca2+-channel activity,control,Mn,Mn + BK,Mn+Vera,727,379,1220,97.2,147.6,Non-contractile embryoid body,Contractile embryoid body,In vivo Mn2+ MRI of myocardial survival and teratoma,VI. In vivo molecular imaging:
8、Reporter Gene,mRNA,Signal,In vivo molecular MRI: Survival,USPIO-monoclonal Ab against HA & c-myc,MRI reporter gene driven by CMV/ubiquitin promoter,Cloning into p2k7-RG lentivirus,Ubc EF1,p2k7(neo or blas),Ubc EF1,(Chung et al, Nat Biotech, 2008, in prep),Validation: FACS,c-myc expression,HA express
9、ion,mESC,hESC,Validation: Immunohistology,Anti c-myc FITC,DAPI,Prussian blue,Validation: In vitro BLI and MRI,mESC,mESC + anti c-myc,mESC-RG + anti c-myc,mESC-RG + anti HA,mESC + anti HA,mESC-RG,hESC + anti c-myc,hESC-RG + anti c-myc,hESC + anti HA,hESC-RG + anti HA,In vivo MRI of hESC-RG,VII. Concl
10、usion,In vivo cellular and molecular MRI: iron-oxide, manganese, and reporter gene Robust labeling Safety profile Dual imaging High sensitivity: longitudinal tracking of location, survival, and teratoma High spatial and temporal resolution: myocardial restoration,Stanford Laboratory for Cardiovascul
11、ar Regeneration,Yang Laboratory Takayasu Arai Jaehoo Chung Rajesh Dash Pratima Kundu Yoriyasu Suzuki Mayumi Yamada Hunter Wang CT Surgery Stephen Hendry Grant Hoyt Ahmed Sheikh Robert Robbins,CV Molecular Biology Thomas Quertermous CV Imaging Feng Cao Chuck Cunningham Tim Doyle Sam Gambhir Michael McConnell John Pauly Masahiro Terashima Joe Wu Esther Xie Pathology Andrew Connolly,CV Intervention Todd Brinton Peter Fitzgerald Alan Yeung Paul Yock Stem Cell Biology Renee Reijo-Pera Micha Drukker Irv Weissman Funding Source NIH AHA CIRM,