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

Nat Commun. 2021 Dec 17;12(1):7334. doi: 10.1038/s41467-021-27562-4.

Abstract

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, CD / metabolism
  • CD4 Antigens / metabolism
  • Cell Cycle*
  • Cell Differentiation
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Size*
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Embryo, Mammalian / metabolism
  • Erythroblasts / cytology
  • Erythroblasts / drug effects
  • Erythroblasts / metabolism
  • Erythrocytes / cytology*
  • Erythrocytes / metabolism*
  • Erythropoiesis*
  • Erythropoietin / administration & dosage
  • Erythropoietin / pharmacology
  • Female
  • Fetus / metabolism
  • Healthy Volunteers
  • Humans
  • Iron / metabolism
  • Liver / embryology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Erythropoietin / metabolism*
  • Receptors, Transferrin / metabolism
  • Reticulocytes / cytology
  • Reticulocytes / drug effects
  • Reticulocytes / metabolism
  • Signal Transduction
  • bcl-X Protein / metabolism

Substances

  • Antigens, CD
  • CD4 Antigens
  • CD71 antigen
  • Receptors, Erythropoietin
  • Receptors, Transferrin
  • bcl-X Protein
  • Erythropoietin
  • Cyclin-Dependent Kinase Inhibitor p27
  • Iron
  • Protein Serine-Threonine Kinases
  • eIF2alpha kinase, mouse