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Stem Cells Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford.

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Presentation on theme: "Stem Cells Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford."— Presentation transcript:

1 Stem Cells Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford

2 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

3 Stem Cells

4 N Engl J Med 2003;349: Phenotypically Characterised Adult Stem Cells

5 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

6 Multinucleate Negative for Connexin 43 Desmosomes Cadherin No integration Menasché P et al. Myoblast transplantation for heart failure. Lancet 2001 Skeletal Myoblast Cell Transplant in Ischaemic Cardiomyopathy

7 Lin - c-kit POS 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:

8 Red=Cardiac Myosin a Green=Cell Nuclei c-kit neg c-kit pos

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10 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:

11 Engraftment does not occur in absence of MI……..

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15 Conclusions Bone marrow-derived lineage negative progenitors regenerate infarcted murine myocardium Autologous “skeletal lineage” progenitors improve cardiac function and survive in infarction scar

16 Bone Marrow Derived Stem Cells : Vascular Injury

17 Bone Marrow Derived Stem Cells : Atherosclerosis

18 Bone Marrow Derived Stem Cells : Transplant Vasculopathy

19 Stem Cells in Human Restenosis ? smc-actin c-kit+ Hibbert et al. Am J Physiol 2004

20 Stem Cells in Human Restenosis ? smc-actin c-kit+ Hibbert et al. Am J Physiol 2004

21 Nude mice 1 day post femoral artery excision Intracardiac medium, human µvascular ECs or EPCs

22 Endothelial Progenitor Cells- Role in Endothelial Maintenance high blood pressure high cholesterol / triglycerides smoking diabetes infections other RISK FACTORS Cytokines e.g. G-CSF STATINSEXERCISE Jonathan Hill, 2004

23 J. Hill et al. NEJM 2003; 348:

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26 Mean ~CK 800 U/L

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28 TOPCARE-AMI: Late MRI follow up

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30 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.

31 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.

32 Saline GM-CSF SalineGM-CSF

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34 EPC Colony-Forming Capacity Following G-CSF J. Hill et al. JACC 2005; in press

35 G-CSF and In-stent Restenosis after MI Kang 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

36 Shirota et al. Biomaterials 2003 vWFFlk-1LDL-Uptake Isolation of EPCs for Stent Delivery

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39 Stem Cells in Interventional Cardiology vascular disease risk, biology, drug therapy cell therapy for post-MI repair cell therapy in PCI

40 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


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