Competitiveness in Mice Deficient for Thrombopoietin and Steel Factor Synergystic Effects on Erythropoiesis, Thrombopoiesis and Stem Cell

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 mice exhibited reduced viability, making up only 2% of the offspring from c-Mpl;Kit intercrosses. The thrombocytopenia and megakaryocytopenia characteristic of c-Mpl mice was unchanged in c-Mpl;Kit mice. However, the number of megakaryocytic colony forming units (CFU-Mk) was significantly reduced, particularly in the spleen. While Kit mice, but not cMpl mice, are anaemic, the anaemia was more severe in double mutant c-Mpl;Kit mice, indicating redundancy between Tpo and SF in erythropoiesis. At the primitive cell level, c-Mpl and Kit mice have similar phenotypes, including reduced progenitors, colony forming units–spleen (CFU-S), and repopulating activities. All of these parameters were exacerbated in double mutant mice. c-Mpl;Kit mice had 8-fold fewer clonogenic progenitor cells and at least 28-fold fewer CFU-S. c-Mpl mice also demonstrated a reduced threshold requirement for non-myeloablative transplant repopulation, a trait previously associated only with Kit mice, and the level of non-myeloablative engraftment was significantly greater in c-Mpl;Kit double mutants. Thus, c-Mpl;Kit mice reveal non-redundant and synergistic effects of Tpo and SF on primitive hematopoietic cells. only. For personal use at PENN STATE UNIVERSITY on February 23, 2013. bloodjournal.hematologylibrary.org From