Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization.
BACKGROUND
Stromal cell-derived factor-1 (SDF-1) is a chemokine considered to play an important role in the trafficking of hematopoietic stem cells. Given the close relationship between hematopoietic stem cells and endothelial progenitor cells (EPCs), we investigated the effect of SDF-1 on EPC-mediated vasculogenesis.


RESULTS
Flow cytometric analysis demonstrated expression of CXCR4, the receptor of SDF-1, by 66+/-3% of EPCs after 7 days in culture. In vitro modified Boyden chamber assay showed a dose-dependent EPC migration toward SDF-1 (control versus 10 ng/mL SDF-1 versus 100 ng/mL SDF-1, 24+/-2 versus 71+/-3 versus 140+/-6 cells/mm2; P<0.0001). SDF-1 attenuated EPC apoptosis (control versus SDF-1, 27+/-1 versus 7+/-1%; P<0.0001). To investigate the effect of SDF-1 in vivo, we locally injected SDF-1 into athymic ischemic hindlimb muscle of nude mice combined with human EPC transplantation to determine whether SDF-1 augmented EPC-induced vasculogenesis. Fluorescence microscopic examination disclosed increased local accumulation of fluorescence-labeled EPCs in ischemic muscle in the SDF-1 treatment group (control versus SDF-1=241+/-25 versus 445+/-24 cells/mm2, P<0.0001). At day 28 after treatment, ischemic tissue perfusion was improved in the SDF-1 group and capillary density was also increased. (control versus SDF-1, 355+/-26 versus 551+/-30 cells/mm2; P<0.0001).


CONCLUSIONS
These findings indicate that locally delivered SDF-1 augments vasculogenesis and subsequently contributes to ischemic neovascularization in vivo by augmenting EPC recruitment in ischemic tissues.
Yamaguchi
Jun-ichi
J
Division of Cardiovascular Research and Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Kusano
Kengo Fukushima
KF
Masuo
Osamu
O
Kawamoto
Atsuhiko
A
Silver
Marcy
M
Murasawa
Satoshi
S
Bosch-Marce
Marta
M
Masuda
Haruchika
H
Losordo
Douglas W
DW
Isner
Jeffrey M
JM
Asahara
Takayuki
T
D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000033:anatomy & histology / Q000254:growth & development; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology*; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors