In healthy individuals, red blood cell (RBC) production matches RBC loss. This remarkable homeostasis is controlled primarily by changes in rates of RBC formation through alterations in EPO concentrations. EPO regulates erythropoiesis by promoting the survival, proliferation, and differentiation of erythroid progenitors (28). Erythro-poiesis encompasses the orderly differentiation of pluripotent, hematopoietic stem cells to mature erythrocytes. Erythropoiesis occurs primarily in the bone marrow and requires 10-14 d for the early progenitor cells, erythroid burst-forming units (BFU-E) to differentiate to erythrocytes. Later stage progenitors, erythroid colony-forming units (CFU-E), require approx 7 d; however, RBC counts increase within 1-2 d of EPO synthesis because cells even later in the differentiation process are present and responsive to EPO. The 1-d to 2-wk time period for RBC formation is relatively fast compared with the life span of an erythrocyte (60-120 d). The temporal mismatch indicates that changes in rates of RBC formation determine RBC counts.
A number of growth factors control the earliest steps of erythroid cell development, including stem cell factor (SCF), granulocyte-macrophage colony stimulating factor (GM-CSF), and several interleukins (ILs) (22). The earliest cell committed to the erythroid lineage, the BFU-E, is weakly stimulated by EPO. Differentiation of BFU-E cells to the CFU-E stage does not absolutely require EPO, as shown in an elegant series of studies with knockout mice that lacked the EPO gene (36). Steps subsequent to the CFU-E stage are EPO-dependent such that EPO is absolutely required for cell survival (37). CFU-E differentiate into additional cell types, ultimately resulting in a reticulocyte. Enucleation of reticulocytes produces mature erythrocytes. The EPO requirement is lost at the last stages (orthochromic erythroblast) of erythropoiesis (21).
EPO acts on erythroid precursor cells through its receptor (EPOR), a transmembrane protein that is a member of the type I cytokine receptor superfamily. Activation of EPOR occurs through homodimerization whereby one EPO molecule binds two EPORs on the surface of the CFU-E (approx 1000 EPORs/cell). EPOR homodimerization activates a number of signal transduction pathways, including Janus Kinase/Signal transducers and activators of transcription (JAK-STAT), phosphatidylinositol 3-kinase (PI3K), and RAS-mitogen-activated protein kinase (MAPK) (21,22). Current research suggests that EPO exerts its control over erythropoiesis by preventing cell apoptosis (programmed cell death), thus allowing more red cell precursors to survive, proliferate, and induce erythroid-specific proteins (37). Some of the apoptotic tendency of ery-throid cells is attributed to proapoptotic molecules produced by hematopoietic cells, macrophages, inflammatory cytokines, and stromal cells. EPO prevents apoptosis by upregulation of antiapoptotic Bcl proteins (Bcl2, BclXL,) and downregulation/inactiva-tion of apoptotic proteins (BAD, a prodeath Bc12 family member, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) forkhead and caspases) (38-43).
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