The Role of EPC in Old Age and Atherosclerosis


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The Role of EPC in Old Age and Atherosclerosis

  1. 1. The Role of EPC in Old Age and Atherosclerosis Dr.Boenjamin Setiawan, Ph.D. 25 October 2008
  2. 2. <ul><li>Number of deaths for leading causes of death, USA, 2005: </li></ul><ul><li>   Heart disease: 652,091 </li></ul><ul><li>   Cancer: 559,312 </li></ul><ul><li>   Stroke (cerebrovascular diseases): 143,579 </li></ul><ul><li>   Chronic lower respiratory diseases: 130,933 </li></ul><ul><li>   Accidents (unintentional injuries): 117,809 </li></ul><ul><li>   Diabetes: 75,119 </li></ul><ul><li>   Alzheimer's disease: 71,599 </li></ul><ul><li>    Influenza/Pneumonia: 63,001 </li></ul><ul><li>   Nephritis, nephrotic syndrome, </li></ul><ul><li>and nephrosis: 43,901 </li></ul><ul><li>   Septicemia: 34,136 </li></ul><ul><ul><li>TOTAL 1.891.470 </li></ul></ul>
  3. 3. TEN LEADING CAUSES OF DEATH IN THE U.S.A., 2004 Heart disease is the leading cause of death of Americans 24 years of age and older, 30.3% or 724,269 annual deaths are due to heart disease. Sixteen percent of those deaths, 115,883, occur in smokers. Cancer is the second leading cause of death causing 23%  or 538,947 deaths. Twenty-three percent of those are lung cancer, 83% of lung cancers occur in smokers and exsmokers (101, 724).
  4. 4. Ten leading causes of death, all WHO member states, 2000 TEN LEADING CAUSES OF DEATH, ALL WHO MEMBER STATES, 2000 2.2% (10) Trachea, Bronchus, Lung Cancers 2.3% (9) Road Traffic Injuries 3.0% (8) Tuberculosis 3.8% (7) Diarrhoeal Diseases 4.4% (6) Perinatal conditions 4.5% (5) Chronic Obstructive Pulmonary Disease 5.3% (4) HIV/AIDS 6.9% (3) Lower Respiratory Infections 9.2% (2) Cerebrovascular Disease 12.4% (1) Ischemic Heart Disease PERCENT OF TOTAL CAUSE
  5. 5. <ul><li>What is a stem cell? (Sources *STEM CELLS: A PRIMER; *STEM CELLS: NIH) A stem cell is a cell with the ability to self-replicate throughout the life of an organism and can differentiate or give rise to many cell types upon stimulation and given the right conditions. Stem cells have the potential to develop into functioning mature cells characteristic of different tissues or organs. In contrast, most cells in the body are already differentiated, have limited lifespans and cannot give rise to other types of cells </li></ul>
  6. 6. Embryonic stem cells are derived from the Inner Cell Mass
  7. 7. Multiple embryos are produced in vitro for clinical purposes. Donated surplus embryos are used as a source of ES cells. These surplus embryos would otherwise be discarded or remain unused How are ES Cells Generated?
  8. 8. Fertilized Embryos Are Allowed to Divide Several Times in Culture
  9. 9. Harvesting ES Cells The blastocyst is the stage of development (~1,000 cells) at which the embryos inner cell mass (ICM) forms. It is the ICM that harbors ES cells. Stem cells exist only fleetingly at this stage of development
  10. 10. Generating an ES Cell Line The trophoblast is removed from the embryo, the inner cell mass is isolated and, using a micropipette, ES cells are extracted and placed in tissue culture. These cells are passaged for many generations until some spontaneously form “immortal” lines
  11. 11. Stem Cells are taken from the Inner Cell Mass at the blastocyst stage and cultured in a Petri disk
  12. 15. Structure of Animal Cell
  13. 16. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  14. 17. The Human Body <ul><li>Consist of 12 Organ Systems </li></ul><ul><li>Consist of 220 types of Tissues </li></ul><ul><li>Consist of 50-100 trillion cells </li></ul><ul><li>Consist of 100 billion neurons </li></ul><ul><li>Consist of 46 chromosomes (22 pairs and x and y chromosomes) </li></ul><ul><li>Consist of 30.000 genes </li></ul><ul><li>Consist of 3,2 billion base pairs </li></ul>seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  15. 18. <ul><li>The cardiovascular circulatory system’s main role is to transport nutrients and oxygen to the 50-100 trillion cells that makes up our body and remove the waste material from the body. </li></ul><ul><li>The most prevalent disease that affects the CVS is: </li></ul><ul><li>Hypertension </li></ul><ul><li>Acute myocardial infarction </li></ul><ul><li>Stroke </li></ul>
  16. 19. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  17. 20. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  18. 21. World’s oldest person celebrates 129 th birthday, died March 2007 According to national records, Hernandez was born on May 3, 1878, in one of the country's central provinces, where she gave birth to 13 children. She now has 60 grandchildren, 80 great-grandchildren and 25 great-great grandchildren.
  19. 22. FIGURE 1. Tissue heterogeneity and stem-cell functionality for homeostasis and repair
  20. 23. FIGURE 2. Variation of maximal lifespan across species. From the following article: Stem cells, ageing and the quest for immortality Thomas A. Rando Nature 441, 1080-1086 (29 June 2006) doi:10.1038/nature04958
  21. 24. Stem cells, ageing and the quest for immortality Thomas A. Rando Influence on Stem Cell Functionality
  22. 25. FIGURE 4. Ageing of stem-cell functionality
  23. 26. ( Circulation. 2007;116:3-5.) © 2007 American Heart Association , Inc. <ul><li>Cardiovascular Biomarkers </li></ul><ul><li>Added Value With an Integrated Approach? </li></ul><ul><li>Wolfgang Koenig, MD, FRCP, FESC From the Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Ulm, Germany. </li></ul>
  24. 28. Figure 1. Origin and differentiation of endothelial progenitor cells . Scheme depicts the potential origin and differentiation of endothelial progenitor
  25. 29. ( Circulation. 2007;115:1285-1295.) © 2007 American Heart Association, Inc. Endothelial Function and Dysfunction Testing and Clinical Relevance John E. Deanfield, MB, BCh, FRCP; Julian P. Halcox, MD, MA, MRCP; Ton J. Rabelink, MD, PhD From the Vascular Physiology Unit (J.E.D., J.P.H.), UCL Institute of Child Health, London, UK; and the Department of Nephrology (T.R.), Leiden University Medical Center, Leiden, The Netherlands. Contemporary Reviews in Cardiovascular Medicine
  26. 30. <ul><li>EPC facilitates angiogenesis </li></ul><ul><li>EPC mobilization and Migration is stimulated by VEGF, Angiopoetin-1, FGF, GM-CSF, MMP-9 and Pharmacological Agents, (Statins) </li></ul>
  27. 32. <ul><li>Figure 1. Left, The quiescent state of the endothelium, where NO (green circles) is generated by the endothelial isoform of nitric oxide synthase (eNOS) in its membrane-bound configuration. The released NO targets cysteine groups in key regulator molecules such as NF B (p50/p65) and the mitochondria, which leads to silencing of cellular processes. Right, The state of endothelial activation where reactive oxygen signaling (red circles) predominates. The ROS such as H2O2 are generated from oxidases as well as the uncoupled state of eNOS. Like NO, the molecules target key regulatory proteins, such as NF B and phosphatases, which leads to activation of the endothelial cells. Such activation can occur physiologically in the context of host defense or pathophysiologically in the presence of cardiovascular risk factors. EC indicates endothelial cells </li></ul>
  28. 33. Figure 2. Sustained ROS signaling induces senescence of endothelial cells. Left, This is reflected in detachment of endothelial cells or parts of the endothelial cell membrane (endothelial microparticles). Right, With increasing age and persisting ROS signaling, the capacity of neighboring endothelial cells to repair the endothelial injury is limited, and vascular integrity becomes dependent on the incorporation of circulating PC
  29. 39. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  30. 40. <ul><li>Major Role: The main role of the nervous system is to relay electrical signals through the body.  The nervous system directs behaviour and movement and, along with the endocrine system, controls physiological processes such as digestion, circulation, etc.  </li></ul><ul><li>The most prevalent diseases that affect the CNS is Stroke, Parkinson’s disease, Alzheimer’s disease, ALS and Autism </li></ul>seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  31. 41. <ul><li>The brain microvascular endothelium constitutes a major exchange area between the blood and the brain: it forms a physiological barrier, known as the blood-brain barrier (BBB), which plays a central role in maintaining cerebral homeostasis. </li></ul>seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.
  32. 42. Spinal Cord Injuries seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D. Hwang Mi-Soon: South Korea Paralyzed 19 years Multipotent adult stem cells injected into her spinal cord Currently: debilitating pain Published in 2005 ( Cytotherapy )
  33. 43. J Am Coll Cardiol, 2003; 42:2081-2082, doi:10.1016/j.jacc.2003.09.016 © 2003 by the American College of Cardiology Foundation EDITORIAL COMMENT Aging of progenitor cells: limitation for regenerative capacity? Stefanie Dimmeler, PhD  ,* and Mariuca Vasa-Nicotera, MD     Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany   Department of Cardiovascular Science, Division of Cardiology, University of Leicester, Leicester, United Kingdom
  34. 44. <ul><li>Journal of Molecular Medicine © Springer-Verlag 200410.1007/s00109-004-0580-x Review </li></ul><ul><li>Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? </li></ul><ul><li>Stefanie Dimmeler1  and Andreas M. Zeiher1 </li></ul><ul><li>(1) Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany </li></ul>
  35. 45. Figure 1 Possible influences of age on endothelial progenitor levels. VEGF = vascular endothelial growth factor.
  36. 46. Fig. 1  Regeneration of the endothelial monolayer after injury. After induction of endothelial injury ( 1 ) two possibilities exist to regenerate the injured endothelial monolayer ( 2 , 3 ). 2 Regeneration by mature endothelial cells which migrate and proliferate to regenerate the endothelial layer. 3 Regeneration by bone marrow derived endothelial progenitor cells
  37. 48. Fig. 3  Possible targets of risk factors for coronary artery disease to reduce circulating endothelial progenitor cells ( 1 – 4 ). Risk factors for coronary artery disease may interfere with hematopoietic stem cells in the bone marrow, reducing mobilization or affecting survival and differentiation of circulating progenitor cells. Additionally, risk factors such as age may also reduce homing by reducing stimulatory factors such as VEGF and the block receptor independent kinases
  38. 50. Competent Marrow compared to Senescent Marrow
  39. 51. Cardiovascular Research 2007 73(2):326-340; doi:10.1016/j.cardiores.2006.06.030 <ul><li>Nutrition, physical activity, and cardiovascular disease: An update </li></ul><ul><li>Louis J. Ignarroa, Maria Luisa Balestrierib and Claudio Napolic,* aDepartment of Molecular Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States bDepartment of Chemical Biology and Physics, Division of Clinical Pathology and Excellence Research Center on Cardiovascular Diseases, Complesso S. Andrea delle Dame, 1st School of Medicine, II University of Naples, Naples 80138 Italy cDepartment of General Pathology, Division of Clinical Pathology and Excellence Research Center on Cardiovascular Diseases, Complesso S. Andrea delle Dame, 1st School of Medicine, II University of Naples, Naples 80138 Italy </li></ul><ul><li>* Corresponding author. Tel./fax: +39 081 293399. Email address: [email_address] </li></ul>
  40. 52. Fig. 2 Different effects of physical exercise on redox status of the cell. Abbreviations: ROS, reactive oxygen species.
  41. 53. Cardiovascular Research Advance Access originally published online on March 18, 2008 Cardiovascular Research 2008 78(3):413-421; doi:10.1093/cvr/cvn081 <ul><li>Vascular repair by endothelial progenitor cells </li></ul><ul><li>Anna Zampetaki, John Paul Kirton and Qingbo Xu* Cardiovascular Division, King's College London, 125 Cold harbour Lane, London SE5 9NU, UK </li></ul><ul><li>* Corresponding author. Tel: +44 20 7848 5322; fax: +44 20 7848 5296. E-mail address : [email_address] </li></ul>
  42. 54. Figure 1 EPC origins. EPCs could be released from bone marrow, fat tissues, vessel wall, especially adventitia and spleen, liver, and intestine, where they form a circulating EPC pool. They can then contribute to the repair of damaged vessels in pathological conditions.
  43. 55. Figure 3 EPC mobilization and differentiation. Schematic graphics summarize cytokines, growth factors, and other mediators inducing EPC release from tissues and homing to the surface of arteries where endothelial cells are damaged. After attachment to the vessel wall, EPCs differentiate into endothelial cells induced by the micro-environment.
  44. 58. <ul><li>EPC facilitates angiogenesis </li></ul><ul><li>EPC mobilization and Migration is stimulated by VEGF, Angiopoetin-1, FGF, GM-CSF, MMP-9 and Pharmacological Agents, (Statins) </li></ul>
  45. 60. Therapeutic Potential of EPC in AMI <ul><li>Figure 2. Therapeutic potential of EPCs. Intracoronary infusion of EPCs in patients with AMI may have the potential to restore myocardial function to the damaged area . </li></ul><ul><li>EPC transplantation increases left ventricular ejection fraction (LVEF), coronary blood flow reserve, and myocardial viability and decreases left ventricular end-systolic volume (LVESV). 66 </li></ul>
  46. 61. How can we slow down Atherosclerosis and old age?? <ul><li>You are what you eat. (CRAN) Consume a healthy diet, Fruits, Vegetables, Fish, lean meat, etc. </li></ul><ul><li>Healthy LIFE-STYLE, no smoking, no alcohol, no stress, regular exercise, keep mentally active, yoga, meditation etc </li></ul><ul><li>Prevent atherosclerosis with statins, control hypertension </li></ul><ul><li>Take ANTI-OXIDANTS (Glisodin) regularly </li></ul><ul><li>Hypothetically: Infuse YOUNG, HEALTHY EPC regularly to keep the endothelial lining clean </li></ul>
  47. 62. Future Perspectives <ul><li>EPCs have been extensively studied in cardiovascular diseases and accumulating evidence highlights their importance in vascular repair and tissue remodelling. </li></ul><ul><li>Despite these encouraging results, there are also several reports on adverse effects in various animal models and there are still many issues concerning the biology of the EPCs that need to be addressed. Numerous studies have underlined the need of increasing EPC numbers to allow sufficient neovascularization and recovery of the ischaemic tissue. Thus, identifying other sources of stem cells and understanding the molecular mechanisms involved in the mobilization, differentiation, and migration of these cells is essential to design effective therapeutic strategies. </li></ul>
  48. 64. <ul><li> Unresolved Questions </li></ul><ul><li>How to define an endothelial progenitor cell?     </li></ul><ul><li>Origin of endothelial progenitor cells?     </li></ul><ul><li>Definition of subpopulations with different functional capacities? </li></ul><ul><li>Signals for EPC homing and differentiation in vivo?     </li></ul><ul><li>Optimization of ex vivo culture conditions to enhance the benefit of cell therapy?     </li></ul><ul><li>Influence of the severity of vascular damage on the contribution of EPCs to regeneration? </li></ul><ul><li>Mechanisms of action?    </li></ul><ul><li>  Transdifferentiation capacity of different progenitor cells?     </li></ul><ul><li>Importance of paracrine effects? </li></ul><ul><li>Effects of OLD AGE on functionality of EPC </li></ul>
  49. 65. Summary <ul><li>Atherosclerosis causes Hypertension, AMI and Stroke. </li></ul><ul><li>Atherosclerosis is still highly prevalent and cost a few hundred billions dollars to society. </li></ul><ul><li>Atherosclerosis can be prevented by diet, regular exercise, healthy life style, drugs (statins, estrogens, anti-oxidants, Glisodin etc.) and EPC </li></ul><ul><li>Glisodin an anti-oxidant stimulating SOD dismutase can reduce atherosclerosis </li></ul><ul><li>Atherosclerosis can theoretically be prevented by the infusion of young, healthy EPC </li></ul><ul><li>Endothelial progenitor cells can be used to maintain the smoothness of the intima and prevent cardiovascular aging </li></ul>
  50. 66. Thank You