THROMBOPOIETIN, THE MPL LIGAND, IS ESSENTIAL FOR FULL MEGAKARYOCYTE DEVELOPMENT

The development of megakaryocytes (MKs) from their marrow precursors i s one of the least understood aspects of hematopoiesis. Current models suggest that early-acting MK colony-stimulating factors, such as inte rleukin (IL) 3 or c-kit ligand, are required for expansion of hematopo ietic progenitors into cells capable of responding to late-acting MK p otentiators, including IL-6 and IL-11. Recently, the Mpl ligand, or th rombopoietin (Tpo), has been shown to display both MK colony-stimulati ng factor and potentiator activities, at potencies far greater than th at of other cytokines. In light of these findings, we tested the hypot hesis that Tpo is absolutely necessary for MK development. In this rep ort we demonstrate that neutralizing the biological activity of Tpo el iminates MK formation in response to c-kit ligand, IL-6, and IL-11, al one and in combination, but that these reagents only partially reduce MK formation in the presence of combinations of cytokines including IL -3. However, despite the capacity of IL-3 to support the proliferation and initial stages of MK differentiation, elimination of Tpo prevents the full maturation of IL-3-induced MK. These data indicate that two populations of MK progenitors can be identified: one that is responsiv e to IL-3 but can fully develop only in the presence of Tpo and a seco nd that is dependent on Tpo for both proliferation and differentiation . Thus, our results strongly suggest that Tpo is the primary regulator of MK development and platelet production.