Optimal erythroid cell production during erythropoietin treatment of mice occurs by exploiting the splenic microenvironment.
In this study, quantitative effects on erythroid cell production by a prolonged recombinant human erythropoietin (rhEpo) treatment of mice are presented. Epo treatments, given subcutaneously (s.c.) twice per day in doses of 0.5 to 500 U per day, were performed under steady-state production conditions. We found striking differences between the behavior of the different erythroid cell compartments (burst-forming unit erythroid [BFU-E], colony-forming unit erythroid [CFU-E] and erythroid precursors), as well as between the microenvironments of bone marrow and spleen. Whereas the total-body BFU-E was not changed by Epo, a redistribution of BFU-E from marrow to spleen occurred, resulting in decreasing marrow and increasing splenic BFU-E numbers. Splenic BFU-E produced CFU-E as much as 8 times more efficiently than marrow BFU-E at 50 U of Epo. At low Epo doses (to 1 U/day) no difference was found. The CFU-E in the spleen produced erythroblasts at a higher efficiency at all Epo doses (1.5 to 5 times). It seems as if this efficiency was higher at low Epo doses. Because of the migration phenomenon and the excellent microenvironment in the spleen, at the highest Epo concentrations nearly 70% of all erythroid cells reside in the spleen. Even at the highest Epo doses, granuloid cell production was not affected. Similar to the BFU-E, total-body granuloid cells remained constant (despite a shift of granulocyte-macrophage progenitors [CFU-GM]) from marrow to spleen; however, these cells did not flourish in the spleen. Under these conditions, 90% of the granuloid precursors were still localized in the marrow. Erythropoietin did not change the transit time of erythroid cells at high Epo doses.
Nijhof
W
W
Laboratory of Physiological Chemistry, State University of Groningen, The Netherlands.
Goris
H
H
Dontje
B
B
Dresz
J
J
Loeffler
M
M
D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006098:Granulocytes / Q000166:cytology; D006400:Hematocrit; D006410:Hematopoiesis / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D012156:Reticulocytes / Q000166:cytology; D013154:Spleen / Q000166:cytology / Q000502:physiology*; D013839:Thiamphenicol / Q000494:pharmacology
D011994:Recombinant Proteins; D004921:Erythropoietin; D013839:Thiamphenicol