The Erythropoietin Receptor Stimulates Rapid Cycling and Formation of Larger Red Cells During Mouse and Human Erythropoiesis [preprint]

Erythroid terminal differentiation entails cell divisions that are coupled to progressive decreases in cell size. EpoR signaling is essential for the survival of erythroid precursors, but it is unclear whether it has other functions in these cells. Here we endowed mouse precursors that lack the EpoR with survival signaling, finding that this was sufficient to support their differentiation into enucleated red cells, but that the process was abnormal. Precursors underwent fewer and slower cell cycles and yet differentiated into smaller red cells. Surprisingly, EpoR further accelerated cycling of early erythroblasts, the fastest cycling cells in the bone marrow, while simultaneously increasing their cell size. EpoR-mediated formation of larger red cells was independent of the established pathway regulating red cell size by iron through Heme-regulated eIF2α kinase (HRI). We confirmed the effect of Epo on red cell size in human volunteers, whose mean corpuscular volume (MCV) increased following Epo administration. This increase persisted after Epo declined and was not the result of increased reticulocytes. Our work reveals a unique effect of EpoR signaling on the interaction between the cell cycle and cell growth. Further, it suggests new diagnostic interpretations for increased red cell volume, as reflecting high Epo and erythropoietic stress

EpoR stimulates rapid cycling and larger red cells during mouse and human erythropoiesis

The erythroid terminal differentiation program couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. Here we use Epor(−/−) mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. We find that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. EpoR-regulation of cell size is independent of established red cell size regulation by iron. High erythropoietin (Epo) increases red cell size in wild-type mice and in human volunteers. The increase in mean corpuscular volume (MCV) outlasts the duration of Epo treatment and is not the result of increased reticulocyte number. Our work shows that EpoR signaling alters the relationship between cycling and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress