Chapter 32: Erythropoiesis

SUMMARY

Production of red cells or erythropoiesis, is a tightly regulated process by which hematopoietic stem cells differentiate into erythroid progenitors and then mature into red cells. Erythropoiesis generates approximately 2 × 10¹¹ new erythrocytes to replace the 2 × 10¹¹ red cells (approximately 1 percent of the total red cell mass) removed from the circulation each day. Red cell production increases several fold after blood loss or hemolysis. When one of the progeny of the multipotential hematopoietic stem becomes committed to the erythroid lineage, this early erythroid progenitor undergoes a series of divisions and concurrent maturation that eventually result in morphologically recognizable erythroblasts. After expulsion of the nucleus, a macrocyte (polychromatophilic when stained by Wright stain, or a reticulocyte if stained with new methylene blue) leaves the marrow. During the first 24 hours in the circulation, reticulocytes lose their residual organelles (mitochondria and ribosomes) through an autophagic process and undergoes reconditioning of the membrane to become mature red blood cells with a morphology of a biconcave disc. Erythropoiesis is controlled by transcription factors and cytokines, the principal ones being GATA 1 and erythropoietin (EPO), which influence the rate of lineage commitment, proliferation, apoptosis, differentiation, and number of divisions from the earliest progenitor to late erythroblasts. The number of red cells produced varies in response to tissue oxygenation that determines the level of the transcription factors, hypoxia-inducible factors (HIF), HIF-1 and HIF-2, the principal regulators of the response to hypoxia. HIFs modulate erythropoiesis by regulation of EPO production, by direct EPO-independent mechanism(s) and facilitating iron availability.

Acronyms and Abbreviations:

BCL11A, a critical switching factor for silencing γ-globin; Bcl-x_L, an antiapoptotic factor; BFU-E, burst-forming units–erythroid; CBP, a coactivator of a transcription factor; CFU-E, colony-forming units-erythroid; CFU-Ec-Kit, growth factor receptor also a protooncogene; CIS, a signal transduction protein that downregulates activity of erythropoietin receptor; CPM, counts per minute; EKLF, erythroid Kruppel-like factor; Emp, erythroblast-macrophage protein; EPO, erythropoietin; EPOR, EPO receptor; FOG, “friend of GATA,” a GATA-1 interacting protein; Gas6, growth arrest-specific 6; GATA-1, transcription factor; HCP, hematopoietic cell phosphatase; Hct, hematocrit; HIF, hypoxia-inducible transcription factor; ICSH, International Committee on Standardization in Hematology; JAK2, a tyrosine kinase that interacts with erythropoietin receptor; KAP1, KRAB-associated protein-1 is a transcriptional cofactor; KRAB-ZFP, one of the 400 human zinc finger protein-based transcription factors; mDia2, a protein that regulates actin and focal adhesion dynamics; miRNAs, microRNAs are small noncoding RNA molecules; NFE-2, a transcription factor, one of the principal regulator of hematopoiesis; Nix, a protein that is expressed during erythropoiesis and regulates mitochondrial apoptosis (autophagy); OS-9, osteosarcoma protein 9; PU.1, a transcription factor; RACK1, receptor of activated protein kinase C; RCM, red cell mass; SCL/TAL1, stem cell leukemia/T-cell acute lymphoblastic leukemia 1 factor; SOCS3, a signal transduction protein (also known as CIS3) that downregulates activity of erythropoietin receptor; VHL, von Hippel-Lindau protein.