The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow

The chemokine SDF-1 plays a central role in the repopulation of the bone ma rrow (BM) by circulating CD34(+) progenitors, but the mechanisms of its act ion remain obscure. To extravasate to target tissue, a blood-borne cell mus t arrest firmly on vascular endothelium. Murine hematopoietic progenitors w ere recently shown in vivo to roll along BM microvessels that display selec tins and integrins. We now show that SDF-1 is constitutively expressed by h uman BM endothelium. In vitro, human CD34(+) cells establish efficient roll ing on P-selectin, E-selectin, and the CD44 ligand hyaluronic acid under ph ysiological shear flow. ICAM-1 alone did not tether CD34(+) cells under flo w but, in the presence of surface-bound SDF-1, CD34(+) progenitors rolling on endothelial selectin rapidly developed firm adhesion to the endothelial surface, mediated by an interaction between ICAM-1 and its integrin ligand, which coimmobilized with SDF-1. Human CD34(+) cells accumulated efficientl y on TNF activated human umbilical cord endothelial cells in the absence of SDF-1, but they required immobilized SDF-1 to develop firm integrin-mediat ed adhesion and spreading. In the absence of selectins, SDF-1 also promoted VLA-4-mediated, Gi protein-dependent tethering and firm adhesion to VCAM-1 under shear flow. To our knowledge, this is the first demonstration that S DF-1 expressed on vascular endothelium is crucial for translating rolling a dhesion of CD34(+) progenitors into firm adhesion by increasing the adhesiv eness of the integrins VLA-4 and LFA-1 to their respective endothelial liga nds, VCAM-1 and ICAM-1.