THROMBOPOIETIN PROMOTES ADHESION OF PRIMITIVE HUMAN HEMATOPOIETIC-CELLS TO FIBRONECTIN AND VASCULAR CELL-ADHESION MOLECULE-1 - ROLE OF ACTIVATION OF VERY LATE ANTIGEN (VLA)-4 AND VLA-5

Thrombopoietin (Tpo), the ligand for c-mpl and a principal regulator o f megakaryocytopoiesis and platelet production, has been demonstrated to stimulate the growth and differentiation of megakaryocyte as well a s multipotent hemopoietic progenitor cells. In the present study we de monstrate that Tpo can stimulate the adhesion of the Mo7e progenitor c ell line to fibronectin (Fn) as well as vascular cell adhesion molecul e-1 through activation of very late antigen (VLA)-4 and VLA-5, adhesio n molecules previously demonstrated to be involved in regulation of st eady state hemopoiesis. Tpo-induced adhesion was concentration depende nt, reached a maximum following 30 min, and appeared to be dependent o n adenylate cyclase, and tyrosine kinase activity. Furthermore, second messenger inhibitors implicated essential and complimentary roles of phosphatidylinositol-3-kinase and protein kinase C in mediating Tpo-in duced adhesion. The ability of Tpo to promote adhesion to fibronectin was comparable to that of IL-3, but less than that of stem cell factor . Unlike the ability of these cytokines to synergistically enhance gro wth of Mo7e as well as normal progenitor cells, no synergy was observe d with regard to their ability to enhance adhesion. Finally, Tpo stimu lated adhesion of primitive (CD34(+)CD38(-)) human bone marrow cells t o fibronectin, predominantly through activation of VLA-5, whereas no s uch effect could be observed on CD34(+)CD38(+) bone marrow cells. Thus , Tpo might play an important role in early hemopoiesis, at least in p art through its ability to promote adhesion through activation of adhe sion molecules on hemopoietic progenitor cells.