Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin.

Abstract

SummaryThrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO -/-mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO -/-mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation ofhematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step ofplatelet production.

Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors

“…At the mature cell level, mutations in c-Mpl and Kit affect the thrombopoietic and erythropoietic lineages, respectively. 7,15,22,23 Moreover, although most other mature lineages are not affected in either single mutant, they both have deficiencies at the stem cell level. 8,[16][17][18]24 We demonstrate here, in double-mutant c-Mpl Ϫ/Ϫ Kit Wv/Wv mice, which lack both Tpo and SF receptors, that these 2 cytokine pathways contribute overlapping and nonredundant actions in mature and multipotential hematopoietic compartments.…”

“…20,21 Tpo or c-Mpl knock-out mice have severe thrombocytopenia, with an 80% reduction in the number of circulating platelets. 7,22,23 c-Mpl Ϫ/Ϫ mice also have decreased numbers of clonogenic progenitor cells in multiple lineages and approximately 7-fold reduced competitive repopulation ability. 8,24 Tpo alone supports HSC survival in vitro 25,26 and acts synergistically with other early-acting factors to induce HSC division.…”

“…5,6 Finally, there is accumulating evidence that early-acting cytokines, including steel factor (SF), Flt3/Flk2 ligand (Flt3L), thrombopoietin (Tpo), interleukin-3 (IL-3), and gp130-associated cytokines such as IL-6 and IL-11 can influence the survival and proliferation of HSCs. This has been shown both by repopulation deficiencies in knock-out mice [7][8][9][10] and by in vitro expansion of primitive cells in the presence of these cytokines. [11][12][13][14] SF and Tpo are 2 important cytokines that affect both primitive and mature hematopoiesis.…”

Major effects of TPO delivered by a single injection of a recombinant adenovirus on prevention of septicemia and anemia associated with myelosuppression in mice: risk of sustained expression inducing myelofibrosis due to immunosuppression

“…Indeed, homozygous TPO or c-mpl knock-out mice exhibit a profound but not lethal thrombocytopenia. 5,6 In vitro and in vivo experiments have shown that TPO is the most potent growth factor for megakaryocyte (MK) differentiation, acting on different developmental stages including MK progenitors, promegakaryoblasts and MK. 7,8 Daily TPO injection to animals including mice and primates increased platelet count up to 10-fold the control value in a few days.…”

hNUDC promotes the cell proliferation and differentiation in a leukemic cell line via activation of the thrombopoietin receptor (Mpl)

“…Numerous experiments have shown that while TPO alone does promote the proliferation and maturation of megakaryocytes during early endomitotic stages, the effect on maturation is muted during the later endomitotic stages. 6,7 However, of most interest was the finding that although mice lacking TPO exhibited a drastic decrease in the number of platelets and cells of the megakaryocytic lineage, these mice remained healthy and their platelets functioned normally. 8 This result implies that TPO-independent mechanisms for megakaryopoiesis and platelet production exist.…”