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CHAPTER 32 the transcription factors, hypoxia-inducible factors (HIF), HIF-1 and HIF-2, the

ERYTHROPOIESIS 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.

Josef T. Prchal and Perumal Thiagarajan

HISTORY
SUMMARY Erythrocytes evolved largely for the purpose of transporting oxygen

to tissues. Thus, the size of the red cell mass and the rate of red cell
Production of red cells or erythropoiesis, is a tightly regulated process by which production must be closely related to supply and demand for oxygen
hematopoietic stem cells differentiate into erythroid progenitors and then in the tissues. Toward the end of the 19th century, French mountain-
mature into red cells. Erythropoiesis generates approximately 2 × 10 new eers and physiologists established that a low tissue tension of oxygen
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erythrocytes to replace the 2 × 10 red cells (approximately 1 percent of the stimulates red cell production. In 1906, Paul Carnot, a professor at
11
1
total red cell mass) removed from the circulation each day. Red cell production the Sorbonne, and Mademoiselle DeFlandre, his associate, suggested
increases several fold after blood loss or hemolysis. When one of the progeny that hypoxia generates a humoral factor capable of stimulating red cell
2
of the multipotential hematopoietic stem becomes committed to the erythroid production. Based on questionable experimental data, an influential
3
lineage, this early erythroid progenitor undergoes a series of divisions and biochemist Friederich Miescher erroneously proposed that marrow
concurrent maturation that eventually result in morphologically recognizable hypoxia directly stimulates red cell production. Finally, in 1950, in an
4
erythroblasts. After expulsion of the nucleus, a macrocyte (polychromatophilic ingenious study on parabiotic rats, Kurt Reissmann provided evidence
when stained by Wright stain, or a reticulocyte if stained with new methylene for the existence of an indirect humoral mechanism. This work, and
work of Erslev and colleagues who demonstrated that the plasma
5,6
blue) leaves the marrow. During the first 24 hours in the circulation, reticu- from anemic rabbits and primates contains an erythrocyte-stimulating
locytes lose their residual organelles (mitochondria and ribosomes) through factor, provided a strong basis for an existence of the factor appropri-
an autophagic process and undergoes reconditioning of the membrane to ately named erythropoietin (EPO). In 1957, Jacobson and coworkers
7
become mature red blood cells with a morphology of a biconcave disc. Erythro- reported that EPO was produced by the kidney, a finding that raised
poiesis is controlled by transcription factors and cytokines, the principal ones the possibility that EPO isolated in adequate amounts might be of ther-
being GATA 1 and erythropoietin (EPO), which influence the rate of lineage apeutic benefit to uremic patients. After EPO cloning and production
commitment, proliferation, apoptosis, differentiation, and number of divisions of recombinant EPO in therapeutic quantities, EPO has proved to have
from the earliest progenitor to late erythroblasts. The number of red cells not only indications for therapy of anemia, but also has extraerythroid
produced varies in response to tissue oxygenation that determines the level of effects that are yet to be fully elucidated, such as its effect on cell growth.
Widespread use of EPO for the treatment of anemia has surpassed orig-
inal expectations.

PHYLOGENY OF RED CELL
Acronyms and Abbreviations: BCL11A, a critical switching factor for silencing PRODUCTION
γ-globin; Bcl-x , an antiapoptotic factor; BFU-E, burst-forming units–erythroid; CBP,
L
a coactivator of a transcription factor; CFU-E, colony-forming units-erythroid; CFU- HEMOGLOBIN AND RED CELLS
Ec-Kit, growth factor receptor also a protooncogene; CIS, a signal transduction pro-
tein that downregulates activity of erythropoietin receptor; CPM, counts per minute; Hemoglobin is present in the most primitive animal forms, such as
EKLF, erythroid Kruppel-like factor; Emp, erythroblast-macrophage protein; EPO, Paramecium and Tetrahymena. Some crustaceans, such as Daphnia, are
erythropoietin; EPOR, EPO receptor; FOG, “friend of GATA,” a GATA-1 interacting pro- capable of developing an oxygen transport system without circulating
8
tein; Gas6, growth arrest-specific 6; GATA-1, transcription factor; HCP, hematopoietic red cells. One interesting exception is an Antarctic ice fish (Chaeno-
9
cell phosphatase; Hct, hematocrit; HIF, hypoxia-inducible transcription factor; ICSH, cephalus aceratus) lacking hemoglobin. These ice fish compensate
International Committee on Standardization in Hematology; JAK2, a tyrosine kinase for the absence of hemoglobin by their unusual nitric oxide metabo-
that interacts with erythropoietin receptor; KAP1, KRAB-associated protein-1 is a lism. 10–12 They have very large hearts and unusually large diameter capil-
transcriptional cofactor; KRAB-ZFP, one of the 400 human zinc finger protein-based laries. This permits a large volume of blood to circulate at high flow rate
transcription factors; mDia2, a protein that regulates actin and focal adhesion and at low vascular pressure because of decreased peripheral resistance.
dynamics; miRNAs, microRNAs are small noncoding RNA molecules; NFE-2, a tran- This permits their survival in the very high oxygen content of Antarctic
scription factor, one of the principal regulator of hematopoiesis; Nix, a protein that is waters. 12
expressed during erythropoiesis and regulates mitochondrial apoptosis (autophagy); An erythroid cell that can synthesize, carry, and protect hemo-
OS-9, osteosarcoma protein 9; PU.1, a transcription factor; RACK1, receptor of acti- globin from oxidation was found only with the development of a cir-
vated protein kinase C; RCM, red cell mass; SCL/TAL1, stem cell leukemia/T-cell acute culatory system. Circulating nucleated erythrocytes first appear in the
lymphoblastic leukemia 1 factor; SOCS3, a signal transduction protein (also known as worms of the phylum Nemertina and in the sessile marine creatures of
CIS3) that downregulates activity of erythropoietin receptor; VHL, von Hippel-Lindau the phylum Phoronida. Erythropoiesis in these primitive invertebrates
protein. takes place near or on the peritoneal surface, derived from endothe-
lial cells. Nonnucleated red cells are observed for the first time in the
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