Erythrocytes

Abstract

The erythrocyte is a highly specialized cell present in the blood designed for the transport of oxygen from the lungs to the body tissues and for the removal and transport of carbon dioxide from the tissues to the lungs. In primates, erythrocytes also clear the blood of complement‐bearing immune complexes and pathogens and exert anti‐inflammatory functions. The blood of an average adult contains approximately 25 million millions of erythrocytes. Maintaining this number of cells constant over time is a major challenge and requires production of as many as 210 billions of new erythrocytes per day (i.e. 24 millions per second). This production is tightly regulated by microenvironmental cues (growth factors) and by proteins present inside the cells (transcription factors). This regulation ensures that erythrocyte production is appropriately increased in response to sudden blood loss.

Key Concepts:

  • Erythrocytes are blood cells responsible for oxygen delivery to all the tissues of the body.

  • Erythrocytes are produced by hematopoietic stem cells present in the bone marrow.

  • Before birth, erythrocytes are derived from stem cell populations present in the yolk sac of the embryo and in the liver of the fetus.

  • Erythropoietin, a cytokine produced by the kidney, is primarily responsible for the regulation of erythrocyte production.

  • The bone marrow also contains several cytokines, which positively or negatively regulate erythrocyte production.

  • Erythrocytes exert their function by expressing on their surface and in their cytoplasm a number of erythroid‐specific proteins.

  • A series of DNA‐binding proteins (the erythroid transcription factors) assure that erythrocytes express adequate amounts of functional proteins.

  • The erythrocyte membrane is plastic and resistant to shear stress allowing the cells to pass through the microvasculature to deliver oxygen. The oxygen delivery function of the erythrocyte is performed by haemoglobin, a cytoplasmic protein whose structure is suited for oxygen transport/exchange.

  • The flexibility/deformability of the erythrocyte membrane is assured by a network between the proteins embedded in its lipid bilayer and the cell cytoskeleton.

  • Blood group antigens are epitopes present on the tertiary (glycosyl residues) or primary (amino‐acid sequence) structure of proteins present on the erythrocyte membrane.

Keywords: erythrocyte; blood groups; anaemia; polycythaemia

Figure 1.

Common erythrocyte shapes. Erythrocytes can assume various shapes depending on their environment, age and possible genetic defects. Some of the more common forms are: (a) discocyte, (b) stomatocyte and (c) echinocyte.

Figure 2.

Polyacrylamide gel electrophoresis of erythrocyte membrane‐associated proteins (a, b) and diagrammatic scheme of the two major complexes formed by some of these proteins on the cell surface (c, d). Integral membrane proteins and those that participate in the membrane skeleton are classified by their electrophoretic mobility in polyacrylamide gel, as detected by staining of (a) carbohydrate with periodic acid–Schiff (PAS) base and (b) protein with Coomassie blue as well as by common names. Proteins are assembled on the red cell membrane in two major complexes, the 4.1 (c) and the Ankirin (d) complex. The intracellular tails of these complexes are linked to a flexible ring of structural proteins (the spectrins) that is in turn associated with the intracellular filaments. These complexes include proteins (Duffy and Kell in the 4.1 complex and glycophorin A (GPA), band 3 and the Rh antigen (RhAg) on the Ankyrin complex), which express minor blood group antigens. (For a detailed description of the proteins and relative minor group antigens present in the 4.1 and Ankyrin complexes see Liu et al. and Reid and Westhoff .)

Figure 3.

The erythrocyte facilitates removal of carbon dioxide (CO2) from the plasma and buffering of the blood. CO2 diffuses into the red cell, where carbonic anhydrase (CA) converts it into bicarbonate (HCO3), which diffuses out of the red cell. Haemoglobin (Hb) releases oxygen (O2) and binds protons (H+). The anion transporter (Band 3) mediates anion exchange in which bicarbonate ions leave and chloride (Cl) ions enter the erythrocyte.

Figure 4.

Haemoglobin oxygen dissociation curve. The saturation of haemoglobin with oxygen is a function of oxygen partial pressure (Po2). The oxygen affinity of haemoglobin depends on the state of haemoglobin oxygenation, increasing with its oxygen saturation. This leads to a characteristic sigmoid‐shaped dissociation curve.

Figure 5.

Flow cytometric (on the left) and functional (on the right) definition of hematopoietic progenitor cells. Flow cytometrical analyses based on the expression of CD34 and CD36 identify several cell populations. Of those, the cells that express CD34 (but not CD36, in red) contain progenitor cells for all the hamatopoietic lineages. Those that express both CD34 and CD36 (in green in the upper quadrant) contain mainly BFU‐E, the progenitor cell, which gives rise in culture to large bursts (>10 000 cells) of erythroblasts. Those that do not express CD34 but express CD36 (in purple in the lower quadrant) contain mainly CFU‐E, the progenitor cell, which gives rise in culture to small erythroid colonies.

Figure 6.

Morphology of the erythroid cells at various stages of maturation as obtained in culture. Cells with similar morphology may be identified in the marrow and in the fetal liver. The detailed description of the various cell types may be found in the ‘Precursor cells’ section. Legend: ProEB, proerythroblast; BasoEB, basophilic erythroblast; and OrthoEB orthochromatic erythroblasts. Modified from Zeuner A, Martelli F, Vaglio S et al. (2012) Concise review: stem cell‐derived erythrocytes as upcoming players in blood transfusion. Stem Cells30(8): 1587–1596. doi: 10.1002/stem.1136.

Figure 7.

Diagrammatic scheme of the cell extrinsic (production of EPO by the kidney) and cell intrinsic (cascade of the events which are initiated by binding of EPO to its receptor, EPO‐R) control of erythroid maturation. Binding of EPO to EPO‐R activates EPO‐R and induce phosphorylation of several signalling molecules. Among these, the most studied is JAK‐2 and is downstream partner STAT‐5. This signalling cascade activates the chromatin modifying complexes and the erythroid‐specific transcription factors, such as GATA1 and EKLF. The chromatin modifying complexes open the configuration of loci, which contain erythroid‐specific genes making the loci accessible to the transcription factors and to the polymerase enzymes. The expression of globin genes is mainly regulated by GATA1, which is that of the membrane proteins by EKLF. For additional information see ‘Molecular control of erythrocyte maturation’ and Table .

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Further Reading

Andrews NC (2009) Pathology of iron metabolism. In: Hoffman R, Benz EJ, Shattil SJ et al. (eds) Hematology: Basic Principles and Practice, 5th edn, pp. 447–452. Philadelphia: Churchill Livingstone.

Beutler E (2009) Production and destruction of erythrocytes. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K and Prchal J (eds) Williams Hematology, vol. 8e, pp. 355–368 New York: McGraw‐Hill.

Beutler E (2010a) Composition of the erythrocyte. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K and Prchal JT (eds) Williams Hematology, vol. 8e. New York: McGraw‐Hill (Access Medicine).

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Papayannopoulou T, Migliaccio AR, Abkowitz JL and D'Andrea A (2009) Biology of erythropoiesis, erythroid differentiation, and maturation. In: Hoffman R, Benz EJ, Shattil SJ et al. (eds) Hematology: Basic Principles and Practice, 5th edn, pp. 276–294. Philadelphia: Churchill Livingstone.

Telen MJ (2009) The mature erythrocyte. In: Wintrobe MM, Greer JP, Foerster J et al. (eds) Wintrobe's Clinical Hematology, 12th edn, p. 126–155. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins.

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Migliaccio, Anna Rita F, and Whitsett, Carolyn(Jan 2013) Erythrocytes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001128.pub2]