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Stem CellsKeith Channon
Department of Cardiovascular MedicineUniversity of Oxford
John Radcliffe Hospital, Oxford
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Adult Stem Cells
• Unique cells that are capable of self-renewal
• Have the ability to differentiate through a committed lineage
• Undergo further development within an adult organism v embryo
• They are multi(pluri)potent v totipotent
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Stem Cells
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N Engl J Med 2003;349:570-82.
Phenotypically Characterised Adult Stem Cells
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Why are Stem Cells Relevant to Interventional Cardiology?
Understanding stem cell biology challenges and informs our understanding of cardiovascular disease
Stem cells may offer new therapeutic approaches in cardiovascular disease
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• Multinucleate
• Negative for
Connexin 43DesmosomesCadherin
• No integration
Menasché P et al. Myoblast transplantation for heart failure. Lancet 2001
Skeletal Myoblast Cell Transplant in Ischaemic Cardiomyopathy
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•Lin- c-kitPOS bone marrow cells from EGFP male mice to myocardium of female C57B6mouse • Injected in peri-infarct tissue 3-5hrs after LAD ligation
Nature 2001;410:701-705
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Red=Cardiac Myosin
a
Green=Cell Nuclei
c-kit negc-kit pos
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•CD117+ CD90+ CD34– MSCs from BM male rats isolated by adhesion to polystyrene, purified by immunoselection,
•Transfected with murine Akt by VSV retrovirus
•Permanent CAL of LAD in female rats
• 60 mins post CAL MSCs injected 5 peri-infarct sites
Nature Medicine 2003;9:1195-1201
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Engraftment does not occur in absence of MI……..
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Conclusions
• Bone marrow-derived lineage negative progenitors regenerate infarcted murine myocardium
• Autologous “skeletal lineage” progenitors improve cardiac function and survive in infarction scar
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Bone Marrow Derived Stem Cells : Vascular Injury
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Bone Marrow Derived Stem Cells : Atherosclerosis
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Bone Marrow Derived Stem Cells :Transplant Vasculopathy
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Stem Cells in Human Restenosis ?
smc-actin c-kit+
Hibbert et al. Am J Physiol 2004
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Stem Cells in Human Restenosis ?
smc-actin c-kit+
Hibbert et al. Am J Physiol 2004
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• Nude mice
• 1 day post femoral artery excision
• Intracardiac medium, human µvascular ECs or EPCs
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Endothelial Progenitor Cells- Endothelial Progenitor Cells- Role in Endothelial MaintenanceRole in Endothelial Maintenance
high blood pressurehigh cholesterol / triglyceridessmokingdiabetesinfectionsother
RISK FACTORSRISK FACTORSCytokinesCytokinese.g. G-CSFe.g. G-CSF
STATINSSTATINSEXERCISEEXERCISE
Jonathan Hill, 2004
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J. Hill et al. NEJM 2003; 348:593-600
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Mean ~CK 800 U/L
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TOPCARE-AMI: Late MRI follow up
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TOPCARE-AMI: Late MRI follow up
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The STIMULATE Trial• Title Multicenter, randomized controlled study of transplantation of bone marrow-
derived progenitor cells into infarct vessels of patients following an acute myocardial infarction, acutely re-vascularised by percutaneous intervention.
• Principal Investigators Prof. Dr. A. M. Zeiher & J.W. Goethe, University of Frankfurt
• Sponsor Cardio-Cell, Zutphen, the Netherlands (parent Cryo Cell using subsid MainGen in Frankfurt )
• Monitoring CorTrial, Berlin
• Objective To assess the safety and efficacy of intracoronary therapy with bone marrow-derived autologous progenitor cells with respect to improvement of myocardial function after an acute myocardial infarction treated by PTCA.
• Design Multi-center,Randomized 1:1
• Primary endpoint improvement of left ventricular dysfunction at rest and during Dobutamine stress, assessed by echocardiography at 4 months.
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THE PRIMATIVE Trial Leicester
Percutaneous Randomised Infusion of Marrow Aspirate To Improve Ventricular Efficiency
• Principal Investigators Tony Gershlick, Nilesh Samani et al.
• Objective Assess the safety and efficacy of intracoronary therapy with bone marrow-derived autologous progenitor cells delivered at salvage PCI (DES) after acute MI, either early or late.
• Design Single-center, Randomized, Placebo-Controlled n=150
• Primary endpoint improvement of left ventricular function, assessed by echocardiography and cardiac MRI at 4 months, and clinical events, up to 5 years.
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Saline
GM-CSF
Saline GM-CSF
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EPC Colony-Forming Capacity Following G-CSF
Day 0 Day 6 Day 14
EP
C-C
FU
0
10
20
30
40*
J. Hill et al. JACC 2005; in press
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G-CSF and In-stent Restenosis after MIKang et al. Lancet 2004
• Patients undergoing PCI with stenting of culprit artery following MI (3 days to 9 months) randomized to G-CSF ± apheresis / IC infusion, control
• No AE’s associated with G-CSF treatment
• At 6 month F/U, improved treadmill time, LVEF, SPECT perfusion in cell infusion group
• In-stent restenosis determined in 7/10 G-CSF treated patients, 0/1 control
• Study terminated
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Shirota et al. Biomaterials 2003
vWF Flk-1 LDL-Uptake
Isolation of EPCs for Stent Delivery
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Stem Cells in Interventional Cardiology
vascular diseaserisk,
biology,drug therapy
cell therapy for post-MI repair
cell therapy in PCI
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Future Directions
• Circulating or Bone Marrow Progenitor Cells?– Harvest or not, which subset?– Statins– Cytokine stimulation to release- e.g. CXCR4, new drugs
• Circulating / Bone Marrow progenitor cells clinical trials- need to be blinded, placebo controlled, with hard end points
• Understanding mechanisms remains critical to evaluating and targeting real benefits