PHYSIOLOGICAL REGULATION OF EARLY AND LATE STAGES OF MEGAKARYOCYTOPOIESIS BY THROMBOPOIETIN

Thrombopoietin (TPO) has recently been cloned and shown to regulate me gakaryocyte and platelet production by activating the cytokine recepto r c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were gene rated by gene targeting. TPO-/- mice have a >80% decrease in their pla telets and megakaryocytes but have normal levels of all the other hema topoietic cell types. A gene dosage effect observed in heterozygous mi ce suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bon e marrow from TPO-/- mice have decreased numbers of megakaryocyte-comm itted progenitors as well as lower ploidy in the megakaryocytes that a re present. These results demonstrate that TPO alone is the major phys iological regulator of both proliferation and differentiation of hemat opoietic progenitor cells into mature megakaryocytes but that TPO is n ot critical to the final step of platelet production.