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+ cell accumulation and development of firm adhesion on TNF-activate...
CD34+ cell accumulation and development of firm adhesion on TNF-activated HUVEC under physiological shear flow. (a) Accumulation of CD34+ cells on intact and TNF-activated HUVEC; effect of EC-associated SDF-1 and blocking mAb’s against E-selectin or VLA-4. Cells were perfused at 1 dyn/cm2 for 45 seconds and then subjected to incremented shear stresses as described in Methods. The number of cells accumulated on the different HUVEC monolayers under the indicated experimental conditions was determined in 4 representative fields of view. Accumulated cells were divided into 2 categories: firmly arrested cells were cells that came to full arrest during accumulation at 1 dyn/cm2 and remained bound and stationary throughout the detachment assay (i.e., at a shear stress of 15 dyn/cm2). Rolling cells were defined as cells that continued to roll on the HUVEC monolayer immediately after tethering at 1 dyn/cm2, or cells that began to roll on the EC at elevated shear stresses and either remained adherent or moved from the field of view. The fractions of arrested or rolling cells among the cells initially accumulated in the field of view are shown in the stacked bars. (b) Resistance to detachment by shear flow of CD34+ cells accumulated at 1 dyn/cm2 on TNF-activated HUVEC. The absolute number of cells accumulated during 1 minute at 1 dyn/cm2 and the number of cells remaining bound at the end of each shear increment (each lasting 5 seconds) are depicted. Values are given as mean ± range of determinations in 4 fields of view. One of 4 independent experiments.