Regulation of Megakaryocytopoiesis by Thrombopoietin

Abstract

It is clear that thrombopoietin is a major hormonal regulator of megakaryocytopoiesis both in vitro and in vivo, and, thus, blood platelet production. Existing data show that the action, chemical nature, and immunologic properties of thrombopoietin from HEK cell culture medium and either endogenously produced or exogenously administered thrombopoietin from animal sources are similar, if not identical. Absolute identity, however, will require comparisons of amino acid sequences of the two preparations. Recent studies have shown that not only does TSF potentiate the action of meg-CSF, but it also has a direct effect on precursor cells to increase the number of megakaryocytic colonies. Other in vitro work showed that TSF stimulates directly the SAChE+ precursor cells to become mature megakaryocytes and causes FMLC to differentiate into megakaryocytic colonies. In vivo, TSF increases megakaryocyte size and number, it causes an elevation in the number of the SAChE+ precursor cells in mouse marrow and increases the maturation of megakaryocytes. Moreover, TSF increases the endomitosis of megakaryocytes in the marrow of mice, along with elevating the number of megakaryocytic colonies in spleens of lethally irradiated bone marrow reconstituted mice. Platelet production is also stimulated in mice by TSF as evidenced by elevated isotopic incorporation into platelets; it increases platelet sizes, and when administered in high doses TSF elevates platelet counts. Full development of colonies of megakaryocytes may depend on two growth factors. It has been hypothesized that one factor, meg-CSF, is effective in clonal expansion whereas a second factor is predominately involved in the endomitotic phase of megakaryocyte development. Multifactoral regulation has been observed for the other cell lineages, and a general proposal for hematopoietic development has been outlined by Iscove. In this scheme, specificity of erythropoietin to erythroid cell lineage is indicated. Previous work, however, shows that recombinant erythropoietin can act as a meg-CSF stimulus, indicating that much is yet to be learned about the action of hematopoietic regulatory factors. Although the present study showed that TSF may in some circumstances stimulate an early cell in the megakaryocytic series, its major effect is probably on the more differentiated population, leading to maturation of megakaryocytes and platelet production.(ABSTRACT TRUNCATED AT 400 WORDS)