Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: Combined consequences for cell therapy in older recipients
Received 18 June 2009; received in revised form 6 August 2009; accepted 26 August 2009. published online 20 November 2009. Corrected Proof
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.
aDivision of Cardiovascular Surgery and Department of Surgery, Toronto General Research Institute and University of Toronto, Toronto, Ontario, Canada
bDepartment of Cardiology, The Second Affiliated Hospital of Guangzhou Medical College, Guangzhou, China
Address 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.
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.
∗ Currently at Panyu He Xian Memorial Hospital, Guangzhou, China.
∗∗ R.D.W. and R.-K.L. contributed equally as co-corresponding authors of this manuscript.
ABSTRACT