Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury.
BACKGROUND
After myocardial infarction (MI), bone marrow-derived cells (BMDCs) are found within the myocardium. The mechanisms determining BMDC recruitment to the heart remain unclear. We investigated the role of stromal cell-derived factor-1alpha (SDF-1) in this process.


RESULTS
MI produced in mice by coronary ligation induced SDF-1 mRNA and protein expression in the infarct and border zone and decreased serum SDF-1 levels. By quantitative polymerase chain reaction, 48 hours after intravenous infusion of donor-lineage BMDCs, there were 80.5+/-15.6% more BDMCs in infarcted hearts compared with sham-operated controls (P<0.01). Administration of AMD3100, which specifically blocks binding of SDF-1 to its endogenous receptor CXCR4, diminished BMDC recruitment after MI by 64.2+/-5.5% (P<0.05), strongly suggesting a requirement for SDF-1 in BMDC recruitment to the infarcted heart. Forced expression of SDF-1 in the heart by adenoviral gene delivery 48 hours after MI doubled BMDC recruitment over MI alone (P<0.001) but did not enhance recruitment in the absence of MI, suggesting that SDF-1 can augment, but is not singularly sufficient for, BDMC recruitment to the heart. Gene expression analysis after MI revealed increased levels of several genes in addition to SDF-1, including those for vascular endothelial growth factor, matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, which might act in concert with SDF-1 to recruit BMDCs to the injured heart.


CONCLUSIONS
SDF-1/CXCR4 interactions play a crucial role in the recruitment of BMDCs to the heart after MI and can further increase homing in the presence, but not in the absence, of injury.
Abbott
J Dawn
JD
Department of Cardiology, Yale University Medical School, New Haven, Conn, USA.
Huang
Yan
Y
Liu
Dingang
D
Hickey
Reed
R
Krause
Diane S
DS
Giordano
Frank J
FJ
D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000080027:Cyclams; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006571:Heterocyclic Compounds / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014161:Transduction, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D001596:Benzylamines; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C088327:plerixafor