The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow
Amnon Peled, … , Tsvee Lapidot, Ronen Alon
Amnon Peled, … , Tsvee Lapidot, Ronen Alon
Published November 1, 1999
Citation Information: J Clin Invest. 1999;104(9):1199-1211. https://doi.org/10.1172/JCI7615.
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Article

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

Abstract

The chemokine SDF-1 plays a central role in the repopulation of the bone marrow (BM) by circulating CD34+ progenitors, but the mechanisms of its action remain obscure. To extravasate to target tissue, a blood-borne cell must arrest firmly on vascular endothelium. Murine hematopoietic progenitors were recently shown in vivo to roll along BM microvessels that display selectins and integrins. We now show that SDF-1 is constitutively expressed by human BM endothelium. In vitro, human CD34+ cells establish efficient rolling on P-selectin, E-selectin, and the CD44 ligand hyaluronic acid under physiological shear flow. ICAM-1 alone did not tether CD34+ cells under flow, 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 efficiently on TNF-activated human umbilical cord endothelial cells in the absence of SDF-1, but they required immobilized SDF-1 to develop firm integrin-mediated 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 SDF-1 expressed on vascular endothelium is crucial for translating rolling adhesion of CD34+ progenitors into firm adhesion by increasing the adhesiveness of the integrins VLA-4 and LFA-1 to their respective endothelial ligands, VCAM-1 and ICAM-1.

Authors

Amnon Peled, Valentin Grabovsky, Liliana Habler, Judith Sandbank, Frenando Arenzana-Seisdedos, Isabelle Petit, Herzl Ben-Hur, Tsvee Lapidot, Ronen Alon

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CD34+ cells and adult PBL express comparable levels of functional P-sele...
CD34+ cells and adult PBL express comparable levels of functional P-selectin ligand. (a) Accumulation of CD34+ cells and PBL perfused in identical numbers over immobilized P-selectin–IgG coated at 2 μg/mL. In control experiments, cells were briefly pretreated with the PSGL-1–blocking mAb KPL-1(αPSGL-1), or were perfused in a cation-free binding medium in the presence of EGTA. (b) Velocities of CD34+ cells and PBL at representative shear stresses on P-selectin–IgG or native (platelet-purified) P-selectin coated on substrates at densities supporting a comparable strength of adhesion of each cell type. Each mean value represents a minimum of 15 cells ± SEM, determined in 2 fields of view. *P < 0.002. **P < 0.016.