THE ROLE OF CS1 MOIETY OF FIBRONECTIN IN VLA4-MEDIATED HEMATOPOIETIC PROGENITOR TRAFFICKING

In vitro the integrin VLA4 mediates the adhesion of haemopoietic proge nitors to bone marrow stroma through an interaction with its ligands V CAM-1 and the CS1 moiety of fibronectin. The VLA4/VCAM-1 pathway has b een implicated in haemopoietic trafficking in vivo since antibodies to both VLA4 and VCAM-1 decrease the homing (lodgement) of transplanted progenitors and mobilize progenitors. However, the role of the CS1 dom ain of fibronectin in progenitor trafficking in vivo has not been expl ored, We studied the effect of competitive inhibition of the VLA4/CS1 pathway on progenitor homing and mobilization in mice. Pre-incubation of bone marrow cells with a CS1 inhibitor did not alter the number of CFU-C or CFU-S12 lodged to the bone marrow of lethally irradiated mice 3 h after transplantation. In addition, continuous administration of a CS1 inhibitor did not increase the number of CFU-C in the peripheral blood. In order to study the role of the VLA4/CS1 pathway in traffick ing of more primitive progenitors we studied whether administration of a CS1 inhibitor mobilized radioprotective cells. In contrast to the e ffect of anti-VCAM-1 which mobilized cells capable of rescuing 100% of lethally irradiated mice, administration of a CS1 inhibitor did not i ncrease the number of radioprotective cells in the peripheral blood. H aemopoietic progenitors also bind to the RGD motif of fibronectin thro ugh an interaction with VLA5 and we therefore also studied the effect of antibodies to VLA5 on progenitor homing and mobilization, Antibody to VLA5 did not alter bone marrow lodgement at 3 h or increase the num ber of circulating haemopoietic progenitors. These studies therefore i mply that, in contrast to VCAM-1, the CS1 moiety of fibronectin is not a significant ligand in VLA4 mediated progenitor trafficking in vivo.