Selectin-mediated recruitment of bone marrow stromal cells in the postischemic cerebral microvasculature.
OBJECTIVE
The therapeutic potential of bone marrow stromal cells (BMSCs) has been demonstrated in different models of stroke. Although it is well established that BMSCs selectively migrate to the site of brain injury, the mechanisms underlying this process are poorly understood. This study addresses the hypothesis that selectins mediate the recruitment of BMSCs into the postischemic cerebral microvasculature.


METHODS
Focal ischemic stroke was induced by middle cerebral artery occlusion and reperfusion. Cell recruitment was monitored using either fluorescent- or radiolabeled BMSCs detected by intravital microscopy or tissue radioactivity. Mice were treated with either a blocking antibody against P- or E-selectin or with the nonselective selectin antagonist, fucoidin. The role of CD44 in cell recruitment was evaluated using BMSCs from CD44 knockout mice.


RESULTS
Middle cerebral artery occlusion and reperfusion was associated with a significantly increased adhesion of BMSCs in cerebral venules compared with sham mice. Immunoneutralization of either E- or P-selectin blocked the middle cerebral artery occlusion and reperfusion-induced recruitment of adherent BMSCs. An attenuated recruitment response in the postischemic hemisphere was also noted after fucoidin treatment or administration of CD44-deficient BMSCs.


CONCLUSIONS
Cerebral vascular endothelium assume a proadhesive phenotype after ischemic stroke that favors the recruitment of BMSCs, which use both P- and E-selectin to home into the infarct site. CD44 may serve as the critical ligand for selectin-mediated BMSC recruitment.
Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.
Gokhan
G
Yilmaz
Shantel
S
Vital
Cigdem Erkuran
CE
Yilmaz
Karen Y
KY
Stokes
J Steven
JS
Alexander
D Neil
DN
Granger
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016130:Immunophenotyping; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055806:Microvessels / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D019007:P-Selectin / Q000378:metabolism / Q000502:physiology*; D011897:Random Allocation; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology
C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D019040:E-Selectin; D018960:Hyaluronan Receptors; D008024:Ligands; D019007:P-Selectin
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