Hematopoiesis is the cellular system which leads to the continuous production of blood cells. This highly complex cellular system is organized into three main compartments: (i) stem cells which are both pluripotent and theorically capable of self renewal; (ii) hematopoietic progenitors which are committed to (only) one cell lineage and are able to proliferate along each particular differentiation pathway; (iii) a maturation compartment in which cells become morphologically identifiable since they synthesize lineage specific proteins. The maturation cell compartment represents the majority of marrow cells. At the present time, the regulation of true stem cells remains poorly understood since these cells are difficult to assay in vitro. In contrast, the regulation of each hematopoietic lineages becomes to be well known. These knowledges are mainly due to two reasons: (i) hematopoietic progenitors can be purified and assayed in culture. Their proliferation and differentiation are strictly dependent upon the presence of hematopoietic growth factors; (ii) these different hematopoietic growth factors have been isolated and their cDNA cloned. Erythropoiesis and megakaryocytopoiesis are two branches of hematopoiesis which lead to the production of RBC and platelets, respectively. These two cell lineages have several common features. However, they markedly differ by their regulation since RBC production depends upon one main stimulus (hypoxia) and, therefore, the terminal erythroid differentiation is regulated by a single growth factor. In contrast, regulation of platelet production may depend on several stimuli such as the platelet mass (homeostasis), inflammation, infection and hypoxia. Therefore, several cytokines are involved in the regulation of megakaryocytopoiesis. In addition, the mechanisms of platelet production are highly complex and, in contrast to all the other hematopoietic lineages where the production of mature cells depends on a single parameter (the proliferation during differentiation), three independent parameters modify thrombopoiesis: a) the number of marrow megakaryocytes (MK) (proliferation of the precursor cells). b) the megakaryocyte volume which directly depends on the MK ploidy. During MK differentiation, MK precursors switch from a mitotic process (DNA duplication followed by cytokinesis) to an endomitotic process (DNA duplication without cytokinesis). Endomitosis is a specific process of the megakaryocytic differentiation and differs from all the other cellular models of polyploidization by the existence of a single polyploid and polylobulated nucleus in each cell. This polyploidization induces a major amplification of the platelet production since it is associated with a parallel increase in the cytoplasmic mass. c) the cytoplasmic maturation. Fragmentation of the MK cytoplasm into platelets requires an important synthesis of cytoplasmic membranes. This membrane development leads to a network of membranes in the MK cytoplasm which will form the future platelet cytoplasmic membranes. Erythropoiesis and megakaryocytopoiesis really begin when a pluripotent stem cell commits toward an early erythroid or MK progenitor, respectively called BFU-E primitive or BFU-MK. Subsequently, these cells proliferate and differentiate giving rise to a continuum of progenitors (BFU-E mature and CFU-E or CFU-MK). Early progenitors of both lineages are regulated by the same growth factors, i.e. IL-3 and GM-CSF. These two growth factors act in synergy with the Steel factor which may be an obligatory cytokine for the erythroid differentiation. Combination of Steel factor with these two factors results in a marked increase in proliferation. Late stages of erythropoiesis are regulated by erythropoietin, an hormone secreted by the kidney, which is a very restricted regulator for the erythroid pathway, but which may also act on the MK differentiation. Response to erythropoietin begins at the BFU-E mature stage of differentiation when the progenitor cells loose their responsiveness to GM-CSF or IL-3. For these two sets of cytokines, there is a sequential action during differentiation. In contrast, although the Steel factor acts on primitive BFU-E, it dramatically enhances the proliferative activity of erythropoietin. Late stages of megakaryocytopoiesis are regulated by several growth factors. The best characterized cytokines acting as this differentiation stages are erythropoietine, IL-6, IL-11, LIF and oncostatin M. These last four cytokines have numerous overlaping biological activities due to their respective receptors which share a common transducing beta chain, the GP130. All these cytokines are able in culture or in vivo to increase (i) the MK ploidy, (ii) the MK size and cytoplasmic maturation, (iii) the MK number at a high dose. However in contrast to erythropoiesis, IL-3, GM-CSF and Steel factor also act on the late stages of MK differentiation and a marked improvement in the cytoplasmic maturation is observed when these different cytokines are combined. The humoral growth factor called thrombopoietin which regulates platelet homeostasis has not been isolated despite 35 years of research. Its existence has been a matter of debate but very recently this factor has been purified and its gene cloned.
