Molecular pathways in bone marrow homing: dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins

The specific retention of intravenously administered hemopoietic cells within bone marrow is a complex multistep process. Despite recent insights, the molecular mechanics governing this process remain largely undefined. This study explored the influence of beta(2)-integrins on the homing to bone marrow and repopulation kinetics of progenitor cells. Both antifunctional antibodies and genetically deficient cells were used. In addition, triple selectin-deficient mice were used as recipients of either deficient (selectin or beta(2)) or normal cells in homing experiments. The homing patterns of either beta(2) null or selectin null cells into normal or selectin-deficient recipients were similar to those of normal cells given to normal recipients. Furthermore, spleen colony-forming units and the early bone marrow repopulating activity for the first 2 weeks after transplantation were not significantly different from those of control cells. These data are in contrast to the importance of beta(2)-integrin and selectins in the adhesion/migration cascade of mature leukocytes. The special bone marrow flow hemodynamics may account for these differences. Although early deaths after transplantation can be seen in recipients deficient in CD18 and selectin, these are attributed to septic complications rather than homing defects. However, when beta(2)- or selectin-null donor cells are treated with anti-alpha(4) antibodies before their transplantation to normal or selectin-deficient recipients, a dramatic inhibition of homing (>90%) was found. The data suggest that the alpha(4)beta(1)/vascular cell adhesion molecule-1 pathway alone is capable of providing effective capture of cells within the bone marrow, but if its function is compromised, the synergistic contribution of other pathways, that is, beta(2)-integrins or selectins, is uncovered.