title: Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors.
abstract: The degree of redundancy between thrombopoietin (Tpo) and steel factor (SF) cytokine pathways in the regulation of hematopoiesis was investigated by generating mice lacking both c-Mpl and fully functional c-Kit receptors. Double-mutant c-Mpl(-/-)Kit(Wv/Wv) mice exhibited reduced viability, making up only 2% of the offspring from c-Mpl(-/-)Kit(Wv/)(+) intercrosses. The thrombocytopenia and megakaryocytopenia characteristic of c-Mpl(-/-) mice was unchanged in c-Mpl(-/-)Kit(Wv/Wv) mice. However, the number of megakaryocytic colony forming units (CFU-Mks) was significantly reduced, particularly in the spleen. While Kit(Wv/Wv) mice, but not c-Mpl(-/-) mice, are anemic, the anemia was more severe in double-mutant c-Mpl(-/-)Kit(Wv/Wv) mice, indicating redundancy between Tpo and SF in erythropoiesis. At the primitive cell level, c-Mpl(-/-) and Kit(Wv/Wv) mice have similar phenotypes, including reduced progenitors, colony forming units-spleen (CFU-Ss), and repopulating activities. All of these parameters were exacerbated in double-mutant mice. c-Mpl(-/-)Kit(Wv/Wv) mice had 8-fold fewer clonogenic progenitor cells and at least 28-fold fewer CFU-Ss. c-Mpl(-/-) mice also demonstrated a reduced threshold requirement for nonmyeloablative transplant repopulation, a trait previously associated only with Kit(W) mice, and the level of nonmyeloablative engraftment was significantly greater in c-Mpl(-/-) Kit(Wv/Wv) double mutants. Thus, c-Mpl(-/-) Kit(Wv/Wv) mice reveal nonredundant and synergistic effects of Tpo and SF on primitive hematopoietic cells.
authors.affiliation: Cancer and Haematology Division, Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Antonchuk
authors.forename: Craig D
authors.initials: CD
authors.lastname: Hyland
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004912:Erythrocytes / Q000166:cytology; D004920:Erythropoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D013154:Spleen / Q000166:cytology; D019089:Stem Cell Factor / Q000378:metabolism; D034061:Thrombopoiesis / Q000502:physiology*; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: C481270:Mpl protein, mouse; D015513:Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D019089:Stem Cell Factor; D013926:Thrombopoietin; D019009:Proto-Oncogene Proteins c-kit