Inhibitors of Erythropoiesis: Effects of Red Cell Extracts on Heme Synthesis and Erythroid Colony Formation in Human Bone Marrow Cultures

Abstract

The hormone erythropoietin is one of the important factors that primarily regulates erythropoiesis in man. However, the control mechanisms of red blood cell (RBC) production involving negative feedback factors are not understood. Evidence that RBC mass has a regulating effect on erythropoiesis can be given by the use of methemoglobinized erythrocytes¹ and by the studies on nephrectomized humans, in which a transfusion of erythrocytes caused a depression of bone marrow erythroblast numbers.² In addition, Kivilaakso and Rytömaa³ first reported, measuring tritiated thymidine incorporation in short-term bone marrow cell cultures, the existence of an inhibitor (erythrocyte chalone) of RBC precursor cell proliferation that was obtainable directly from mature erythrocytes. Using a similar in vitro technique, several investigators^4,5 confirmed their findings. We have also reported the presence of an erythropoietic inhibitory substance, which is of low-molecular weight, in sera of normal and hypertransfused-polycythemic rabbits.^6,7 These findings suggest the existence of RBC-specific inhibitors that may control the proliferation of erythroid precursor cells as negative feedback factors. However, little is known of the mode of action of such inhibitors and how RBC-specific inhibitors take part in erythropoiesis in patients with various hematological disorders.