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

Antonchuk, J; Hyland, CD; Hilton, DJ; Alexander, WS

Author(s): Antonchuk, J; Hyland, CD; Hilton, DJ; Alexander, WS;
Details: Publication Year 2004-09-01,Volume 104,Issue #5,Page 1306-1313
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: The degree of redundancy between thrombopoietin (Tpo) and steel factor (SF) cytokine pathways in the regulation of hematopolesis was investigated by generating mice lacking both c-MpI and fully functional c-Kit receptors. Double-mutant c-MpI(-/-)Kit(Wv/Wv) mice exhibited reduced viability, making up only 2% of the offspring from c-MpI(-/-)Kit(Wv/+) intercrosses. The thrombocytopenia and megakaryocytopenia characteristic of c-MpI(-/-) mice was unchanged in c-MpI(-/-)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-MpI(-/-) mice, are anemic, the anemia was more severe in double-mutant c-MpI(-/-)Kit(Wv/Wv) mice, indicating redundancy between Tpo and SF in erythropoiesis. At the primitive cell level, c-MpI(-/-) 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-MpI(-/-)Kit(Wv/Wv) mice had 8-fold fewer clonogenic progenitor cells and at least 28-fold fewer CFU-Ss. c-MpI(-/-)mice also demonstrated a reduced threshold requirement for nonmyeloalblative transplant repopulation, a trait previously associated only with Kit(W) mice, and the level of nonmyeloablative engraftment was significantly greater in c-MpI(-/-)Kit(Wv/Wv) double mutants. Thus, c-MpI(-/-)Kit(Wv/Wv) mice reveal nonreduridant and synergistic effects of Tpo and SF on primitive hematopoietic cells. (C) 2004 by The American Society of Hematology.
Publisher: AMER SOC HEMATOLOGY
Keywords: PRIMITIVE HEMATOPOIETIC PROGENITORS; COLONY-STIMULATING FACTOR; EARLY ACTING CYTOKINES; C-MPL; IN-VITRO; SPLEEN-COLONY; SELF-RENEWAL; TYROSINE PHOSPHORYLATION; RESIDUAL MEGAKARYOCYTE; PLATELET PRODUCTION
Publisher's Version: https://doi.org/10.1182/blood-2004-04-1522
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2004-09-01 12:00:00