Medizinische Klinik

, Volume 104, Issue 4, pp 287–295 | Cite as

Perspektiven regenerativer Mechanismen bei Herz-Kreislauf-Erkrankungen am Beispiel endothelialer Progenitorzellen

ÜBERSICHT

Zusammenfassung

Kardiovaskuläre Erkrankungen sind die häufigste Todesursache in der westlichen Welt. Die zugrundeliegende Erkrankung ist in aller Regel die Atherosklerose, die maßgeblich durch eine Schädigung der gefäßauskleidenden Endothelzellschicht gekennzeichnet ist. Die Wiederherstellung eines gesunden Gefäßendothels zur Prävention und Therapie kardiovaskulärer Erkrankungen stellt damit ein wichtiges Konzept im Rahmen der regenerativen Medizin dar.

In dieser Arbeit wird ein Überblick über den derzeitigen Stand der regenerativen Mechanismen bei Herz-Kreislauf-Erkrankungen am Beispiel endothelialer Progenitorzellen gegeben, und die perspektivische Bedeutung der regenerativen Medizin wird am Beispiel der Gefäßgesundheit dargestellt.

Schlüsselwörter:

Endotheliale Progenitorzellen Atherosklerose Regenerative Medizin Mobilisation Koronare Herzkrankheit 

Perspectives of Regenerative Mechanisms in Cardiovascular Disease Spotlighting Endothelial Progenitor Cells

Abstract

Cardiovascular diseases are the most common cause of death in the Western world. In general, the underlying disease is atherosclerosis, which is hallmarked by deterioration of the endothelial monolayer. Restoration of an intact endothelial monolayer for prevention and therapy of cardiovascular diseases is one key concept of regenerative medicine.

This article offers a review of state-of-the-art regenerative mechanisms in cardiovascular disease spotlighting endothelial progenitor cells, and further features the perspectives of regenerative medicine in vascular biology.

Key Words:

Endothelial progenitor cells Atherosclerosis Regenerative medicine Mobilization Coronary heart disease 

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References

  1. 1.
    Lusis AJ. Atherosclerosis. Nature 2000;407:233–41.PubMedCrossRefGoogle Scholar
  2. 2.
    Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 2000;95:952–8.PubMedGoogle Scholar
  4. 4.
    Reyes M, Dudek A, Jahagirdar B, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002;109:337–46.PubMedGoogle Scholar
  5. 5.
    Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999–1007.PubMedCrossRefGoogle Scholar
  6. 6.
    Sieveking DP, Buckle A, Celermajer DS, et al. Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J Am Coll Cardiol 2008;51:660–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Ingram DA, Mead LE, Tanaka H, et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004;104:2752–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin Y, Weisdorf DJ, Solovey A, et al. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000;105:71–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28:1584–95.PubMedCrossRefGoogle Scholar
  10. 10.
    Hur J, Yoon CH, Kim HS, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004;24:288–93.PubMedCrossRefGoogle Scholar
  11. 11.
    Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol 2006;7:333–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Cottler-Fox MH, Lapidot T, Petit I,et al. Stem cell mobilization. Hematology Am Soc Hematol Educ Program 2003:419–37.Google Scholar
  13. 13.
    Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood 2005;106:1901–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest 2000;106:1331–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Hattori K, Dias S, Heissig B, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 2001;193:1005–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Hattori K, Heissig B, Wu Y, et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med 2002;8:841–9.PubMedGoogle Scholar
  17. 17.
    Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 2003;102:1340–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Strehlow K, Werner N, Berweiler J, et al. Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 2003;107:3059–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Yamaguchi J, Kusano KF, Masuo O, et al. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003;107:1322–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Laufs U, Urhausen A, Werner N, et al. Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. Eur J Cardiovasc Prev Rehabil 2005;12:407–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004;109:220–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Aicher A, Heeschen C, Mildner-Rihm C, et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003;9:1370–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Ozuyaman B, Ebner P, Niesler U, et al. Nitric oxide differentially regulates proliferation and mobilization of endothelial progenitor cells but not of hematopoietic stem cells. Thromb Haemost 2005;94:770–2.PubMedGoogle Scholar
  24. 24.
    Kollet O, Dar A, Shivtiel S, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 2006;12:657–64.PubMedCrossRefGoogle Scholar
  25. 25.
    Aicher A, Kollet O, Heeschen C, et al. The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche. Circ Res 2008;103:796–803.PubMedCrossRefGoogle Scholar
  26. 26.
    Gill M, Dias S, Hattori K, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 2001;88:167–74.PubMedGoogle Scholar
  27. 27.
    Aicher A, Rentsch M, Sasaki K, et al. Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res 2007;100:581–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Massberg S, Schaerli P, Knezevic-Maramica I, et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 2007;131:994–1008.PubMedCrossRefGoogle Scholar
  29. 29.
    Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593–600.PubMedCrossRefGoogle Scholar
  30. 30.
    Fischer JC, Kudielka BM, Kanel R von, et al. Bone marrow-derived progenitor cells are associated with psychosocial determinants of health after controlling for classical biological and behavioral cardiovascular risk factors. Brain Behav Immun 2009:in press.Google Scholar
  31. 31.
    Lippincott MF, Desai A, Zalos G, et al. Predictors of endothelial function in employees with sedentary occupations in a worksite exercise program. Am J Cardiol 2008;102:820–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Umemura T, Soga J, Hidaka T, et al. Aging and hypertension are independent risk factors for reduced number of circulating endothelial progenitor cells. Am J Hypertens 2008;21:1203–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001;89:E1–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Muller-Ehmsen J, Braun D, Schneider T, et al. Decreased number of circulating progenitor cells in obesity: beneficial effects of weight reduction. Eur Heart J 2008;29:1560–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Steiner S, Niessner A, Ziegler S, et al. Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis 2005;181:305–10.PubMedCrossRefGoogle Scholar
  36. 36.
    Werner N, Wassmann S, Ahlers P, et al. Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Res Cardiol 2007;102:565–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Bartunek J, Vanderheyden M, Vandekerckhove B, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation 2005;112:Suppl:I178–83.PubMedGoogle Scholar
  38. 38.
    Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004;363:751–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Inoue T, Sata M, Hikichi Y, et al. Mobilization of CD34-positive bone marrow-derived cells after coronary stent implantation: impact on restenosis. Circulation 2007;115:553–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Aoki J, Serruys PW, Van Beusekom H, et al. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol 2005;45:1574–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Co M, Tay E, Lee CH, et al. Use of endothelial progenitor cell capture stent (Genous Bio-Engineered ® Stent) during primary percutaneous coronary intervention in acute myocardial infarction: intermediate- to long-term clinical follow-up. Am Heart J 2008;155:128–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhou Z, Shi S, Song M, et al. Development of transgenic endothelial progenitor cell-seeded stents. J Biomed Mater Res 2009:in press.Google Scholar
  43. 43.
    Kalka C, Masuda H, Takahashi T, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000;97:3422–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Kawamoto A, Gwon HC, Iwaguro H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001;103:634–7.PubMedGoogle Scholar
  45. 45.
    Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J Am Coll Cardiol 2004;44:1690–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Schachinger V, Erbs S, Elsasser A, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006;27:2775–83.PubMedCrossRefGoogle Scholar
  48. 48.
    Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006;113:1287–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006;355:1199–209.PubMedCrossRefGoogle Scholar
  51. 51.
    Seeger FH, Tonn T, Krzossok N, et al. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J 2007;28:766–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Cho HJ, Kim HS, Lee MM, et al. Mobilized endothelial progenitor cells by granulocyte-macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation. Circulation 2003;108:2918–25.PubMedCrossRefGoogle Scholar
  53. 53.
    Urao N, Okigaki M, Yamada H, et al. Erythropoietin- mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide funcsynthase activation and prevent neointimal hyperplasia. Circ Res 2006;98:1405–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Walter DH, Rittig K, Bahlmann FH, et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002;105:3017–24.PubMedCrossRefGoogle Scholar
  55. 55.
    Werner N, Priller J, Laufs U, et al. Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol 2002;22:1567–72.PubMedCrossRefGoogle Scholar
  56. 56.
    Ince H, Petzsch M, Kleine HD, et al. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation 2005;112:3097–106.PubMedCrossRefGoogle Scholar
  57. 57.
    Ellis SG, Penn MS, Bolwell B, et al. Granulocyte colony stimulating factor in patients with large acute myocardial infarction: results of a pilot dose-escalation randomized trial. Am Heart J 2006;152:1051. e9-14.PubMedCrossRefGoogle Scholar
  58. 58.
    Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006;113:1983–92.PubMedCrossRefGoogle Scholar
  59. 59.
    Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006;295:1003–10.PubMedCrossRefGoogle Scholar
  60. 60.
    Pitchford SC, Furze RC, Jones CP, et al. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4:62–72.PubMedCrossRefGoogle Scholar
  61. 61.
    Bauersachs J, Widder JD. Endothelial dysfunction in heart failure. Pharmacol Rep 2008;60:119–26.PubMedGoogle Scholar
  62. 62.
    Valgimigli M, Rigolin GM, Fucili A, et al. CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation 2004;110:1209–12.PubMedCrossRefGoogle Scholar
  63. 63.
    Badorff C, Brandes RP, Popp R, et al. Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003;107:1024–32.PubMedCrossRefGoogle Scholar
  64. 64.
    Yeh ET, Zhang S, Wu HD, et al. Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 2003;108:2070–3.PubMedCrossRefGoogle Scholar
  65. 65.
    Nygren JM, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004;10:494–501.PubMedCrossRefGoogle Scholar
  66. 66.
    Iwasaki H, Kawamoto A, Ishikawa M, et al. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation 2006;113:1311–25.PubMedCrossRefGoogle Scholar
  67. 67.
    Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006;355:1222–32.PubMedCrossRefGoogle Scholar
  68. 68.
    Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001;108:399–405.PubMedGoogle Scholar
  69. 69.
    Wang CH, Ting MK, Verma S, et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J 2006;152:1051. e1-8.CrossRefGoogle Scholar
  70. 70.
    Wang CH, Verma S, Hsieh IC, et al. Enalapril increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system. J Mol Cell Cardiol 2006;41:34–43.PubMedCrossRefGoogle Scholar
  71. 71.
    Yao EH, Fukuda N, Matsumoto T, et al. Effects of the antioxidative beta-blocker celiprolol on endothelial progenitor cells in hypertensive rats. Am J Hypertens 2008;21:1062–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Hill JM, Syed MA, Arai AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1643–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Sharpless NE, Depinho RA. How stem cells age and why this makes us grow old. Nat Rev 2007;8:703–13.CrossRefGoogle Scholar
  74. 74.
    Beausejour C. Bone marrow-derived cells: the influence of aging and cellular senescence. In: Kauser K, Zeiher A-M, eds. Handbook of experimental pharmacology. Berlin-Heidelberg: Springer, 2007: 67–88.Google Scholar
  75. 75.
    Wassmann S, Werner N, Czech T, et al. Improvement of endothelial function by systemic transfusion of vascular progenitor cells. Circ Res 2006;99:e74–83.PubMedCrossRefGoogle Scholar
  76. 76.
    George J, Afek A, Abashidze A, et al. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2005;25:2636–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Boyle AJ, Whitbourn R, Schlicht S, et al. Intra-coronary high-dose CD34+ stem cells in patients with chronic ischemic heart disease: a 12-month follow-up. Int J Cardiol 2006;109:21–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Yoo KJ, Kim HO, Kwak YL, et al. Autologous bone marrow cell transplantation combined with off-pump coronary artery bypass grafting in patients with ischemic cardiomyopathy. Can J Surg 2008;51:269–75.PubMedGoogle Scholar
  79. 79.
    Hirsch A, Nijveldt R, Van Der Vleuten PA, et al. Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute myocardial infarction treated with primary PCI: pilot study of the multicenter HEBE trial. Cathet Cardiovasc Interv 2008;71:273–81.CrossRefGoogle Scholar
  80. 80.
    Kim JB, Sebastiano V, Wu G, et al. Oct4-induced pluripotency in adult neural stem cells. Cell 2009;136:411–9.PubMedCrossRefGoogle Scholar

Copyright information

© Urban & Vogel, Muenchen 2009

Authors and Affiliations

  1. 1.Medizinische Klinik und Poliklinik II, Kardiologie, Pulmologie und AngiologieUniversitätsklinikum BonnBonnGermany
  2. 2.Medizinische Klinik und Poliklinik IIUniversitätsklinikum BonnBonnGermany

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