Normal HematopoiesisErythropoietin-regulated oxidative stress negatively affects enucleation during terminal erythropoiesis

•Erythropoietin (Epo) induces reactive oxygen species (ROS) production in early-stage erythroblasts.•Oxidative status is correlated with CD71 expression and the uptake of iron and transferrin.•The ROS level decreases in the late stages of terminal erythropoiesis.•The ROS scavenger promotes enucleation.

Differentiating erythroblasts are exposed to an oxidative environment. The dynamics of oxidative status during terminal erythropoiesis and how they affect cell differentiation in response to erythropoietin (Epo) are unclear. Here, we show that Epo induces reactive oxygen species (ROS) production in the early stages of terminal erythropoiesis. The levels of ROS correlate with CD71 surface expression and the uptake of iron and transferrin. ROS decreases in the late stages of terminal erythropoiesis, when the cells are preparing for enucleation. Consistently, treatment of erythroblasts with a low dose (5 mM) of N-acetyl-cysteine (NAC), a ROS scavenger, promotes enucleation. However, a high dose (20 mM) of NAC leads to significant cell death. Our study reveals an important function of Epo in regulating the dynamics of oxidative status and enucleation.