Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial
progenitor cells for neovascularization
Tomono Takahashi, Christoph Kalka, Haruchika Masuda, Donghui Chen, Marcy Silver, Marianne Kearney, Meredith Magner, Jeffrey M. Isner
& Takayuki Asahara
Departments of Medicine (Cardiology) and Biomedical
Research, St. Elizabeth's Medical Center, Tufts University School of Medicine
, 736 Cambridge Street, Boston Massachusetts
02135-2997, USA
Correspondence should be addressed to Jeffrey M. Isner or Takayuki Asahara
Endothelial progenitor cells (EPCs) have been isolated from circulating
mononuclear cells in human peripheral blood and shown to be incorporated into
foci of neovascularization, consistent with postnatal vasculogenesis1. We determined whether endogenous stimuli (tissue ischemia) and
exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor,
GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic
tissues. The development of regional ischemia in both mice and rabbits increased
the frequency of circulating EPCs. In mice, the effect of ischemia-induced
EPC mobilization was demonstrated by enhanced ocular neovascularization after
cornea micropocket surgery in mice with hindlimb ischemia compared with that
in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating
EPCs were further augmented after pretreatment with GM-CSF, with a corresponding
improvement in hindlimb neovascularization. There was direct evidence that
EPCs that contributed to enhanced corneal neovascularization were specifically
mobilized from the bone marrow in response to ischemia and GM-CSF in mice
transplanted with bone marrow from transgenic donors expressing -galactosidase
transcriptionally regulated by the endothelial cell-specific Tie-2 promoter.
These findings indicate that circulating EPCs are mobilized endogenously in
response to tissue ischemia or exogenously by cytokine therapy and thereby
augment neovascularization of ischemic tissues.
-galactosidase
transcriptionally regulated by the endothelial cell-specific Tie-2 promoter.
These findings indicate that circulating EPCs are mobilized endogenously in
response to tissue ischemia or exogenously by cytokine therapy and thereby
augment neovascularization of ischemic tissues.
