Thrombopoietin: more than a lineage-specific megakaryocyte growth factor

In the past two years thrombopoietin (TPO) has been cloned, its effects on cells of the megakaryocytic lineage have been described in detail and its use in clinical settings of myelosuppressive therapy has begun. Moreover, the mechanisms by which the hormone binds to its receptor have been studied in detail, and the intracellular pathways employed during TPO signaling have been extensively explored. Although most workers in the field predicted that TPO would be lineage-specific, with physiologic effects limited to megakaryocytes and platelets, several features of Mpl biology suggest its influence on hematopoiesis may be more widespread than initially anticipated. To test this possibility, we and others have begun to explore whether TPO affects development of the hematopoietic stem cell. In suspension culture, TPO alone can support the survival of a fraction of hematopoietic stem cells but does not lead to their proliferation. However, in combination with interleukin 3 or stem cell factor, TPO accelerates hematopoietic stem cell entry into the cell cycle over that seen with these early-acting cytokines alone, increases the number of subsequent cell divisions per unit time and results in the output of far greater numbers of colony-forming cells of all lineages. Conclusions from these in vitro studies are supported by two types of in vivo experiments. The administration of TPO to either normal or myelosuppressed animals causes an expansion of colony-forming unit (CFU)-megakaryocyte, CFU-granulocyte-macrophage, CFU-granulocyte/erythroid/macrophage/megakaryocyte and BFU-E, and elimination of TPO or its receptor by genetic engineering results in a substantial decrease in the numbers of these progenitors in both the marrow and spleen. It is thus becoming clear that the effects of TPO extend beyond that of a megakaryocyte-specific factor and suggest that the hematopoietic effects of administration of the hormone may be greater than initially anticipated.