Effects of continuous stem cell factor administration on normal and erythropoietin-stimulated murine hemopoiesis: experimental results and model analysis.
The aim of this study was to determine how stem cell factor (SCF) modifies hemopoietic cell production. First we determined the effects of a prolonged SCF administration on murine hemopoiesis and analyzed the results by a mathematical simulation model of hemopoiesis in order to explain the data. Subsequently we investigated the effects of simultaneous coadministration of SCF+erythropoietin (Epo), to see how effects of early and late cytokines superimpose. SCF administration during 14 days induced a proliferative wave through the hemopoietic system; colony forming units-granulocyte macrophage (CFU-GM), burst forming units-erythroid (BFU-E) and colony forming units erythroid (CFU-E) were the first to be augmented, followed by their respective progeny, ultimately leading to increased blood cell numbers. Despite continued treatment most cell numbers returned to normal values in 14 days, colony forming units-spleen (CFU-S), however, remained elevated. This wave pattern could be explained within the framework of a previously established mathematical model of hemopoiesis, if it was assumed that SCF affected the cycling status of primitive cells and if regulatory feedback loops of erythroid and myeloid progenitors on these cells were also allowed. Simultaneous SCF and Epo administration led to synergistic effects on CFU-E numbers and hematocrit values at moderate Epo doses. At high Epo doses, however, this was less pronounced. We conclude that SCF increases the input into committed hemopoietic lineages, where late acting cytokines can induce further amplification.
de Haan
G
G
Groningen Institute for Drug Studies, Department of Hematology, University of Groningen, The Netherlands.
Dontje
B
B
Nijhof
W
W
Loeffler
M
M
D000818:Animals; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D019089:Stem Cell Factor
D016298:Hematopoietic Cell Growth Factors; D019089:Stem Cell Factor; D004921:Erythropoietin