Do the preclinical effects of thrombopoietin correlate with its in vitro properties?

In the short time since its cloning, much has been learned of the in vitro properties of thrombopoietin (TPO). In addition to effects on the differentiation of megakaryocytes, TPO has also been shown to stimulate the proliferation of megakaryocytic progenitor cells, colony-forming units-megakaryocytes (CFU-MK), to act in synergy with interleukin 3 or c-kit ligand and erythropoietin (Epo) to stimulate the development of early and the generation of late erythroid progenitor cells, and to affect the rate of entry into the cell cycle and proliferative capacity of hematopoietic stem cells. An important question posed by these observations, for both TPO and for hematopoietic research in general, is whether the in vitro effects of a cytokine are mirrored by its preclinical and clinical biology. The results of recent studies in mice and nonhuman primates will be presented which have attempted to address this issue. In normal animals, TPO increases the numbers of marrow and spleen CFU-granulocyte/erythroid/macrophage/megakaryocyte, CFU-MK, CFU-GM and BFU-E, but its effects in the peripheral blood are limited to marked increases in the platelet count. The reason for widespread progenitor cell effects, yet stable leukocyte and erythrocyte blood counts, is likely the predominant regulatory effects of G-CSF and Epo; in the absence of elevated levels of the lineage-dominant regulator of each of these cell types, expanded progenitor cell numbers are not translated into increased peripheral blood counts. However, in states of increased blood cell demand such as follows myelosuppressive therapy, elevated levels of Epo and G-CSF allow the effects of TPO on erythropoiesis and myelopoiesis to become manifest. The administration of TPO to myelosuppressed animals is associated with not only greatly expanded hematopoietic progenitor cell recovery, but also improvement in platelet, red cell and leukocyte nadir levels and greatly accelerated recovery of all three cell lineages. These results indicate that the panhematopoietic properties of TPO identified by in vitro culture techniques correlate well with its effects in animals. The results of ongoing clinical trials should soon establish whether these conclusions can be extended to patient care.