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; received in revised form 6 August 2009; accepted 26 August 2009. published online 20 November 2009.

Objective

Cell therapy has received much attention for its potential to regenerate ischemic organs, but initial clinical trials in aged patients did not replicate the dramatic benefits recorded in preclinical studies with young animals. This study was designed to improve our understanding of age-related changes in the response to ischemic injury and the regenerative capacity of implanted cells in the context of cell therapy for older recipients.

Methods and Results

Restoration of regional perfusion after hind limb femoral artery ligation was impaired (P < .05) in old (vs young) rats, reflecting approximately 50% reductions in circulating endothelial progenitor cells and the release of vascular endothelial growth factor/basic fibroblast growth factor. Bone marrow stromal cells from young or old donors implanted into the ischemic hind limbs of young or old rats restored regional perfusion. Specifically, we documented significantly greater (P < .05) angiogenic potential in young (vs old) donor cells when recipient age was controlled and greater (P < .05) regenerative responses in young (vs old) recipients when donor cell age was controlled. Contributing to these differences were significantly greater survival in young (vs old) donor cells (in vitro and after implantation) and about 2-fold more production of vascular endothelial growth factor/basic fibroblast growth factor and mobilization of endogenous endothelial progenitor cells in young (vs old) rats in response to ischemia.

Conclusions

The outcome of cell therapy in older recipients is determined by a combination of age effects on the donor cells and on the recipients' endogenous responses. Donor cell age and recipient age are equally important contributors to the outcome of cell therapy; thus, novel biointerventions will need to target both components of the process.

CTSNet classification: 29, 38, 39.1, 39.2

Abbreviations and Acronyms: ANOVA, analysis of variance, bFGF, basic fibroblast growth factor, BMSC, bone marrow stromal cell, BrdU, bromodeoxyuridine, ELISA, enzyme-linked immunosorbent assay, EPC, endothelial progenitor cell, FITC, fluorescein isothiocyanate, LDPI, laser Doppler perfusion image, TUNEL, terminal dUTP nick-end labeling, VEGF, vascular endothelial growth factor

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 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

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