The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen.

Abstract

Selective lodgement or homing of transplanted hemopoietic stem cells in the recipient's bone marrow (BM) is a critical step in the establishment of long-term hemopoiesis after BM transplantation. However, despite its biologic and clinical significance, little is understood about the process of homing. In the present study, we have concentrated on the initial stages of homing and explored the functional role in vivo of some of the adhesion pathways previously found to mediate in vitro adhesion of hemopoietic cells to cultured BM stroma. We have found that homing of murine hemopoietic progenitors of the BM of lethally irradiated recipients at 3 h after transplant was significantly reduced after pretreatment of the donor cells with an antibody to the integrin very late antigen 4 (VLA4). This inhibition of marrow homing was accompanied by an increase in hemopoietic progenitors circulating in the blood and an increased uptake of these progenitors by the spleen. Similar results were obtained by treatment of the recipients with an antibody to vascular cell adhesion molecule 1 (VCAM-1), a ligand for VLA4. Furthermore, we showed that administration of the same antibodies (anti-VLA4 or anti-VCAM-1) to normal animals causes mobilization of hemopoietic progenitors into blood. These data suggest that hemopoietic cell lodgement in the BM is a regulatable process and can be influenced by VLA4/VCAM-1 adhesion pathway. Although additional molecular pathways are not excluded and may be likely, our data establish VCAM-1 as a BM endothelial addressin, analogous to the role that mucosal addressin cell adhesion molecule (MAdCAM) plays in lymphocyte homing. Whether splenic uptake of hemopoietic progenitors is passive or controlled through different mechanisms remains to be clarified. In addition, we provide experimental evidence that homing and mobilization are related phenomena involving, at least partly, similar molecular pathways.

The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner

“…33,34 Indeed CD49d/VCAM-1 interactions have been shown to play an important role in the homing of progenitor cells back to the bone marrow. 35,36 It has previously been shown that CD49d expressed on neutrophils mediates interactions with VCAM-1 29 ; therefore, it is likely that neutrophil release is VCAM-1 dependent. However, there is also a precedent in the literature, in a model of chronic vasculitis, for CD49d/CD29-mediated neutrophil adhesion to be independent of VCAM-1.…”

β1 integrins are not required for the maintenance of lymphocytes within intestinal epithelia

“…Given the functional expression of b 1 integrins by mouse IEL, we sought to determine their importance in maintaining lymphocytes within the small intestinal epithelium. As b 1 deficiency is embryonically lethal and b 1 integrins are required for stem cell colonization of the BM [15][16][17], we utilized a model, recently described by Brakebusch et al [18], in which b 1 gene deletion is induced in lethally irradiated mice that have been reconstituted with BM derived from inducible b 1 -knockout mice [18]. Previous results have demonstrated that the number and phenotype of T cells in the spleen, lymph nodes, and peripheral blood of these mice is normal as is the homing and localization of b 1 -deficient T cells to the spleen, lymph nodes, and Peyer's patches [18].…”

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

“…Furthermore, in vivo experiments demonstrated that the pretreatment of animals with antia4 monoclonal antibodies (mAbs) inhibited engraftment of HSC during subsequent transplantation, and infusion of antia4 mAbs caused a robust mobilization of HSC into the peripheral blood (Papayannopoulou & Nakamoto, 1993;Papayannopoulou et al, 1995). More recent studies demonstrated that a chemokine, stromal cell-derived factor-1 [SDF-1, also termed CXCL12 according to a new classification system (Zlotnik & Yoshie, 2000)], plays a key role in the trafficking and homing of CD34 + cells to the marrow (Wright et al, 2002).…”