Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins

Abstract

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 ␤ 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 ␤ 2 ) or normal cells in homing experiments. The homing patterns of either ␤ 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 colonyforming 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 ␤ 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 ␤ 2 -or selectin-null donor cells are treated with anti-␣ 4 antibodies before their transplantation to normal or selectin-deficient recipients, a dramatic inhibition of homing (>90%) was found. The data suggest that the ␣ 4 ␤ 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, ␤ 2 -integrins or selectins, is uncovered. IntroductionRestriction of the developing hemopoietic cells to certain anatomic sites within the body, that is, the extravascular spaces of the bone marrow (BM), signifies a unique microenvironment capable of providing not only anchorage to hemopoietic cells, but of transmitting signals enabling their proliferation and differentiation. The relationship of hemopoietic cells with their microenvironment is a highly dynamic one allowing further expansion on demand and, depending on the stimuli, the movement of cells in and out of their microenvironment. The ability of intravenously administered cells to re-establish connections within the BM environment is a clinically exploited example of that flexibility. As the sinusoidal endothelial cells separate the extravascular space from the circulation, intravenously administered cells need first to tether to the sinusoidal endothelium, then to firmly anchor themselves within the extravascular space through reversible adhesion and transmigration steps. Although several insights regarding the molecular pathways that guide these processes have been obtained, our knowledge of this complex process remains incomplete. Early reports suggest that galactose-and mannose-specific lectins (present...

Inflammation and skeletal metastasis

“…Interestingly, the expression of a4b1 integrin was shown to be required for hematopoietic cell homing to the bone marrow. 155 VCAM-1 expression can be induced in cancer cells by proinflammatory cytokines such as IL-1. 156 Furthermore, as outlined above, the activation of a4b1 integrin induced the recruitment of CD11b þ /Gr1 þ myeloid infiltrate into tumors, which enhanced inflammation and metastasis.…”

The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization

“…The origin of mice deficient in granulocyte colony-stimulating factor receptor (G-CSFR Ϫ/Ϫ ), metalloproteinase 9 (MMP-9 Ϫ/Ϫ ), monocyte chemoattractant protein 1 (MCP-1 Ϫ/Ϫ ), or CD18 (CD18 Ϫ/Ϫ ) and selectin (EϩLϩP Ϫ/Ϫ ) has been mentioned previously. 31,32 Both Tpo Ϫ/Ϫ mice and double knockout Tpo Ϫ/Ϫ , G-CSFR Ϫ/Ϫ mice were kindly provided by Dr K. Kaushansky (University of California at San Diego). Nonobese/severe combined immunodeficient (NOD/SCID) mice were from Jackson Laboratories and Rag2 Ϫ/Ϫ from Taconic (Oxnard, CA).…”

Trafficking of Multipotent Mesenchymal Stromal Cells from Maternal Circulation Through the Placenta Involves Vascular Endothelial Growth Factor Receptor-1 and Integrins

“…Different ␣ and ␤ subunits are expressed in limited combinations to produce different ligand specificities [21]. Integrins mediate the homing of transplanted hematopoietic stem cells to the bone marrow [22], as well as the recruitment of inflammatory cells to sites of inflammation [23]. Thus, they may be involved in maternal cell mobilization across the placenta.…”