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  • Interaction between NO and superoxide appears to be an important feature of vascular disease models. However, its importance in human atherosclerosis is unclear.
  • Stem Cells - Biology ppt slides

    1. 1. Stem Cells Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford For more slides click here DOWNLOAD THIS SLIDE
    2. 2. Adult Stem Cells <ul><li>Unique cells that are capable of self-renewal </li></ul><ul><li>Have the ability to differentiate through a committed lineage </li></ul><ul><li>Undergo further development within an adult organism v embryo </li></ul><ul><li>They are multi(pluri)potent v totipotent </li></ul>
    3. 3. Stem Cells
    4. 4. N Engl J Med 2003;349:570-82. Phenotypically Characterised Adult Stem Cells
    5. 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. 6. <ul><li>Multinucleate </li></ul><ul><li>Negative for </li></ul><ul><li>Connexin 43 </li></ul><ul><li>D esmosomes </li></ul><ul><li>C adherin </li></ul><ul><li>No integration </li></ul>Skeletal Myoblast Cell Transplant in Ischaemic Cardiomyopathy Menasché P et al. Myoblast transplantation for heart failure. Lancet 2001
    7. 7. <ul><li>Lin - c- kit POS bone marrow cells from EGFP male mice to myocardium of female C57B6 mouse </li></ul><ul><li>Injected in peri-infarct tissue 3-5hrs after LAD ligation </li></ul>Nature 2001;410:701-705
    8. 8. Red=Cardiac Myosin a Green=Cell Nuclei c-kit neg c-kit pos
    9. 10. <ul><li>CD117+ CD90+ CD34– MSCs from BM male rats isolated by adhesion to polystyrene, purified by immunoselection, </li></ul><ul><li>Transfected with murine Akt by VSV retrovirus </li></ul><ul><li>Permanent CAL of LAD in female rats </li></ul><ul><li>60 mins post CAL MSCs injected 5 peri-infarct sites </li></ul>Nature Medicine 2003;9:1195-1201
    10. 11. Engraftment does not occur in absence of MI……..
    11. 15. Conclusions <ul><li>Bone marrow-derived lineage negative progenitors regenerate infarcted murine myocardium </li></ul><ul><li>Autologous “skeletal lineage” progenitors improve cardiac function and survive in infarction scar </li></ul>
    12. 16. Bone Marrow Derived Stem Cells : Vascular Injury
    13. 17. Bone Marrow Derived Stem Cells : Atherosclerosis
    14. 18. Bone Marrow Derived Stem Cells : Transplant Vasculopathy
    15. 19. Stem Cells in Human Restenosis ? smc-actin c-kit+ Hibbert et al. Am J Physiol 2004
    16. 20. Stem Cells in Human Restenosis ? smc-actin c-kit+ Hibbert et al. Am J Physiol 2004
    17. 21. <ul><li>Nude mice </li></ul><ul><li>1 day post femoral artery excision </li></ul><ul><li>Intracardiac medium, human µ vascular ECs or EPCs </li></ul>
    18. 22. Endothelial Progenitor Cells- Role in Endothelial Maintenance Jonathan Hill, 2004 high blood pressure high cholesterol / triglycerides smoking diabetes infections other RISK FACTORS Cytokines e.g. G-CSF STATINS EXERCISE
    19. 23. J. Hill et al. NEJM 2003; 348:593-600
    20. 26. Mean ~ CK 800 U/L
    21. 28. TOPCARE-AMI: Late MRI follow up
    22. 29. TOPCARE-AMI: Late MRI follow up
    23. 30. The STIMULATE Trial <ul><li>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. </li></ul><ul><li>Principal Investigators Prof. Dr. A. M. Zeiher & J.W. Goethe, University of Frankfurt </li></ul><ul><li>Sponsor Cardio-Cell, Zutphen, the Netherlands (parent Cryo Cell using subsid MainGen in Frankfurt ) </li></ul><ul><li>Monitoring CorTrial, Berlin </li></ul><ul><li>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. </li></ul><ul><li>Design Multi-center,Randomized 1:1 </li></ul><ul><li>Primary endpoint improvement of left ventricular dysfunction at rest and during Dobutamine stress, assessed by echocardiography at 4 months. </li></ul>
    24. 31. THE PRIMATIVE Trial Leicester <ul><li>P ercutaneous R andomised I nfusion of M arrow A spirate T o I mprove V entricular E fficiency </li></ul><ul><li>Principal Investigators Tony Gershlick, Nilesh Samani et al. </li></ul><ul><li>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. </li></ul><ul><li>Design Single-center, Randomized, Placebo-Controlled n=150 </li></ul><ul><li>Primary endpoint improvement of left ventricular function, assessed by echocardiography and cardiac MRI at 4 months, and clinical events, up to 5 years. </li></ul>
    25. 32. Saline GM-CSF Saline GM-CSF
    26. 34. EPC Colony-Forming Capacity Following G-CSF J. Hill et al. JACC 2005; in press
    27. 35. G-CSF and In-stent Restenosis after MI Kang et al. Lancet 2004 <ul><li>Patients undergoing PCI with stenting of culprit artery following MI (3 days to 9 months) randomized to G-CSF ± apheresis / IC infusion, control </li></ul><ul><li>No AE’s associated with G-CSF treatment </li></ul><ul><li>At 6 month F/U, improved treadmill time, LVEF, SPECT perfusion in cell infusion group </li></ul><ul><li>In-stent restenosis determined in 7/10 G-CSF treated patients, 0/1 control </li></ul><ul><li>Study terminated </li></ul>
    28. 36. Shirota et al. Biomaterials 2003 vWF Flk-1 LDL-Uptake Isolation of EPCs for Stent Delivery
    29. 39. Stem Cells in Interventional Cardiology vascular disease risk, biology, drug therapy cell therapy for post-MI repair cell therapy in PCI
    30. 40. Future Directions <ul><li>Circulating or Bone Marrow Progenitor Cells? </li></ul><ul><ul><li>Harvest or not, which subset? </li></ul></ul><ul><ul><li>Statins </li></ul></ul><ul><ul><li>Cytokine stimulation to release- e.g. CXCR4, new drugs </li></ul></ul><ul><li>Circulating / Bone Marrow progenitor cells clinical trials- need to be blinded, placebo controlled, with hard end points </li></ul><ul><li>Understanding mechanisms remains critical to evaluating and targeting real benefits </li></ul>