Erythropoietin regulation of red blood cell production: from bench to bedside and back

Abstract

More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure–function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new “designer” drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.

The Role of PI3K/AKT and MAPK Signaling Pathways in Erythropoietin Signalization

“…Subsequently, arising erythroid lineage differentiates from the proerythroblast stage, followed by basophilic, polychromatophilic, and orthochromatic erythroblast with a gradually decreased number of EPOR. Beginning from BFU-E stage and ending in the orthochromatic phase, EPO accompanies differentiating cells throughout their maturation and induces transcriptional reprogramming [ 6 ]. The final product of erythropoiesis is red blood cells with its characteristic biconcave shape ideally adapted for transport of respiration gases.…”

Psoriasis: Recent progress in molecular‐targeted therapies

“…Most of cytokines and interferons transmit their signal via type I and II cytokine receptors lacking an enzymatic activity and JAKs, which are nonreceptor tyrosine kinases. [170][171][172][173][174][175][176][177][178][179] . JAK subsequently phosphorylates and activates signal transducer and activators of transcription (STATs).…”

“…Most of cytokines and interferons transmit their signal via type I and II cytokine receptors lacking an enzymatic activity and JAKs, which are nonreceptor tyrosine kinases 170‐179 …”

Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine

“…Human erythropoietin (EPO) is a peptide hormone produced in the fetal liver during early development and the kidneys in the human adult body. As a major hematopoietic growth factor (HGF), it regulates bone marrow erythropoiesis by promoting the daily massive production (200 billion) of RBCs full of hemoglobin A (α 2 β 2 ), that carry oxygen and transfer it from the lungs to tissues [1][2][3][4][5][6] (Figure 1). In terms of structure, EPO is a glycoprotein consisting initially of 193 aa that include an N-terminal 27 aa signaling peptide.…”