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

• Published in: Nature communications Vol. 12; no. 1; p. 7334
• Main Authors: Hidalgo, Daniel, Bejder, Jacob, Pop, Ramona, Gellatly, Kyle, Hwang, Yung, Maxwell Scalf, S., Eastman, Anna E., Chen, Jane-Jane, Zhu, Lihua Julie, Heuberger, Jules A. A. C., Guo, Shangqin, Koury, Mark J., Nordsborg, Nikolai Baastrup, Socolovsky, Merav
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/1; 631/80/641; 631/80/83; 692/698/233; 96; 96/21; 96/31; 96/35; 96/95; Adult; Animals; Antigens, CD - metabolism; bcl-X Protein - metabolism; CD4 Antigens - metabolism; Cell Cycle; Cell Differentiation; Cell division; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Size; Cell Survival; Cycles; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Diagnostic systems; Embryo, Mammalian - metabolism; Erythroblasts; Erythroblasts - cytology; Erythroblasts - drug effects; Erythroblasts - metabolism; Erythrocytes - cytology; Erythrocytes - metabolism; Erythropoiesis; Erythropoietin; Erythropoietin - administration & dosage; Erythropoietin - pharmacology; Female; Fetus - metabolism; Healthy Volunteers; Humanities and Social Sciences; Humans; Hypoxia; Iron - metabolism; Liver - embryology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Models, Biological; multidisciplinary; Protein Serine-Threonine Kinases - metabolism; Receptors, Erythropoietin - metabolism; Receptors, Transferrin - metabolism; Reticulocytes; Reticulocytes - cytology; Reticulocytes - drug effects; Reticulocytes - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Survival
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27562-4

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. Maturing erythroblasts become smaller with every cell division. Here, the authors show that Epo stimulation promotes cell division and also generates larger red cells, and that this occurs in mouse and human cells, suggesting that red cell size could be a diagnostic marker for hypoxic stress.