The Journal of Thoracic and Cardiovascular Surgery
Volume 139, Issue 5 , Pages 1286-1294.e2 , May 2010

Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: Combined consequences for cell therapy in older recipients

  • Yufeng Zhuo, MD

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
    • Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical College, Guangzhou, China
  • ,
  • Shu-Hong Li, MD, MSc

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
  • ,
  • Min-Sheng Chen, MD

      Affiliations

    • Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical College, Guangzhou, China
  • ,
  • Jun Wu, MD

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
  • ,
  • Heather Y. McDonald Kinkaid, MSc

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
  • ,
  • Shafie Fazel, MD, PhD

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
  • ,
  • Richard D. Weisel, MD

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
    • R.D.W. and R.-K.L. contributed equally as co-corresponding authors of this manuscript.
  • ,
  • Ren-Ke Li, MD, PhD

      Affiliations

    • Division of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
    • R.D.W. and R.-K.L. contributed equally as co-corresponding authors of this manuscript.
    • Corresponding Author InformationAddress for reprints: Ren-Ke Li, MD, PhD, Department of Surgery, Division of Cardiovascular Surgery, Toronto General Research Institute, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College St, Toronto, ON, Canada M5G 1L7.

Received 18 June 2009 ,Revised 6 August 2009 ,Accepted 26 August 2009.

References 

  1. Al-Khaldi A, Al-Sabti H, Galipeau J, Lachapelle K. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg. 2003;75:204–209
  2. Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest. 2006;116:1865–1877
  3. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–685
  4. Tomita S, Mickle DA, Weisel RD, Jia ZQ, Tumiati LC, Allidina Y, et al. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg. 2002;123:1132–1140
  5. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210–1221
  6. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, et al. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol. 2007;50:1761–1767
  7. Dimmeler S, Vasa-Nicotera M. Aging of progenitor cells: limitation for regenerative capacity?. J Am Coll Cardiol. 2003;42:2081–2082
  8. Heeschen C, Lehmann R, Honold J, Assmus B, Aicher A, Walter DH, et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004;109:1615–1622
  9. Rivard A, Fabre JE, Silver M, Chen D, Murohara T, Kearney M, et al. Age-dependent impairment of angiogenesis. Circulation. 1999;99:111–120
  10. Scheubel RJ, Zorn H, Silber RE, Kuss O, Morawietz H, Holtz J, et al. Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol. 2003;42:2073–2080
  11. Edelberg JM, Tang L, Hattori K, Lyden D, Rafii S. Young adult bone marrow–derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circ Res. 2002;90:E89–E93
  12. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003;108:457–463
  13. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433:760–764
  14. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow–derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434–438
  15. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343–353
  16. Ryan NA, Zwetsloot KA, Westerkamp LM, Hickner RC, Pofahl WE, Gavin TP. Lower skeletal muscle capillarization and VEGF expression in aged vs. young men. J Appl Physiol. 2006;100:178–185
  17. Wagatsuma A. Effect of aging on expression of angiogenesis-related factors in mouse skeletal muscle. Exp Gerontol. 2006;41:49–54
  18. Gennaro G, Menard C, Michaud SE, Rivard A. Age-dependent impairment of reendothelialization after arterial injury: role of vascular endothelial growth factor. Circulation. 2003;107:230–233
  19. Pouzet B, Vilquin JT, Hagege AA, Scorsin M, Messas E, Fiszman M, et al. Factors affecting functional outcome after autologous skeletal myoblast transplantation. Ann Thorac Surg. 2001;71:844–850
  20. Nakamura Y, Yasuda T, Weisel RD, Li RK. Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function. Am J Physiol Heart Circ Physiol. 2006;291:H939–H947
  21. Fazel S, Chen L, Weisel RD, Angoulvant D, Seneviratne C, Fazel A, et al. Cell transplantation preserves cardiac function after infarction by infarct stabilization: augmentation by stem cell factor. J Thorac Cardiovasc Surg. 2005;130:1310
  22. Kim C, Li RK, Li G, Zhang Y, Weisel RD, Yau TM. Effects of cell-based angiogenic gene therapy at 6 months: persistent angiogenesis and absence of oncogenicity. Ann Thorac Surg. 2007;83:640–646
  23. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005;102:11474–11479
  24. Sykes M, Nikolic B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature. 2005;435:620–627

 Disclosures: Financial support was provided by grants to R.-K.L. from the Canadian Institutes of Health Research (MOP14795) and Eileen Mercier and ING Canada Inc and to R.W. from the Heart and Stroke Foundation of Ontario (T5809, T6148). R.-K.L. is a Career Investigator of the Heart and Stroke Foundation of Canada and holds a Canada Research Chair in cardiac regeneration.

 Dr Zhuo's current affiliation is Panyu He Xian Memorial Hospital, Guangzhou, China.

PII: S0022-5223(09)01171-4

doi: 10.1016/j.jtcvs.2009.08.052

The Journal of Thoracic and Cardiovascular Surgery
Volume 139, Issue 5 , Pages 1286-1294.e2 , May 2010