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

Abstract

IntroductionTransplanted human hematopoietic stem cells must retain specific adhesive capacity to interact with the vascular endothelium that lines the bone marrow (BM) (1-3). The mechanisms by which these cells home to and engraft the BM are still obscure. Murine hematopoietic progenitors (HPCs) have been shown to interact in vivo with both P-selectin and E-selectin on vascular endothelium of murine BM (4). In addition, VCAM-1 has been shown to support rolling of HPC on BM endothelium in the absence of endothelial selectins (4). Nevertheless, optimal recruitment of HPC to the BM requires the combined action of both selectins and VCAM-1 (5). Thus, the initiation of primary rolling adhesion of blood-borne cells to the lining of the BM microvessels under shear flow is critical for the recruitment of HPC to the BM. HPC rolling on BM endothelium is likely to be accompanied by a coordinated sequence of adhesive and activation events leading to cell arrest, a key step in the successful extravasation of blood-borne cells to extravascular beds (6, 7). In these prior studies, the mechanisms by which HPCs develop firm adhesion to BM endothelium in the presence of physiological shear flow have not been elucidated.We recently established a key role for the chemokine SDF-1 and its receptor CXCR4 in murine BM engraftment by human severe combined immunodeficiency (SCID) repopulating stem cells (8). In light of the growing evidence that chemokines can regulate the arrest of leukocytes on blood vessels through integrin-dependent interactions with IgSF ligands, we asked whether SDF-1 regulates CD34 + progenitors interaction with BM endothelium, and if so, how. We now report that human BM endothelium constitutively expresses high levels of SDF-1. Using in vitro flow chamber assays, we have tested the specific effects of SDF-1 on the ability of human cord blood CD34 + progenitors to initiate rolling interactions and arrest on human vascular endothelium and on isolated endothelial receptors, including E-selectin, P-selectin, ICAM-1, and VCAM-1, which have all been shown to be constitutively expressed on both murine and human BM endothelium (9). Our results suggest that SDF-1 is a key player 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 ...

CXCR4 chemokine receptors (CD184) and α4β1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis)

“…A CXCR4-negative progenitor cell line (Kasumi-1) did not display pseudoemperipolesis. The SDF-1/ CXCR4 axis and binding of a4b1 and a5b1 integrins has recently been demonstrated to be involved in the transendothelial migration of haematopoietic progenitor cells (HPC) (Mohle et al, 1998;Jo et al, 2000;Peled et al, 2000), in the rolling and arrest of HPC on vascular endothelial cells under shear flow (Peled et al, 1999b), and in human HPC mobilization and homing (Prosper et al, 1998;Peled et al, 1999a;Kollet et al, 2001). It has also been demonstrated that HSC are uniquely selective in their chemotactic responsiveness to SDF-1, suggesting that this chemokine is the key factor for homing of HSC to the marrow that cooperates with integrins, in particular a4b1 integrins (Wright et al, 2002).…”

“…It has also been demonstrated that HSC are uniquely selective in their chemotactic responsiveness to SDF-1, suggesting that this chemokine is the key factor for homing of HSC to the marrow that cooperates with integrins, in particular a4b1 integrins (Wright et al, 2002). Peled et al (1999b) suggested that SDF-1 expression on vascular endothelium initiates HSC homing to the marrow, as demonstrated by shear flow adhesion assays and anti-SDF-1 staining of marrow microvessels. Our study extends this concept by demonstrating that stromal cells are active players in HSC migration.…”

Homing of Cancer Cells to the Bone

“…This indicates that primitive bone marrow cells migrate to the bone in an integrin mediated SDF-1/protein kinase C signaling dependent mechanism [62]. Engraftment studies on NOD/SCID also shows that SDF1/CXCR4 activates several integrins such as VLA-4, VLA-5; and to a lesser degree, LFA-1 on CD34+ progenitor cells which enhances the process of engraftment [63,64]. Incorporation and colocalization of CXCR4 and Rac-1 into lipid rafts could enhance the chemotaxis of hematopoietic stem progenitor cells (HSPC) towards the bone [65].…”

SDF-1α/CXCL12 enhances retroviral-mediated gene transfer into immature subsets of human and murine hematopoietic progenitor cells

“…Stromal-derived factor 1 (SDF-1a, also called CXCL12) belongs to the a-chemokine family and is constitutively expressed by bone marrow (BM) endothelial cells. 26,27 SDF-1 exerts most of its biological effects by binding to the G-protein-coupled CXCR4 receptor, which is expressed on many cell types including some CD34 þ CD38 À cells. 28,29 SDF-1 and CXCR4 are central to hematopoiesis, chemotaxis, and engraftment of hematopoietic stem and progenitor cells.…”