Erythrocytes

Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. RBCs carry hemoglobin, and the shape allows efficient oxygen transport. Billions of RBCs are produced daily, as the life span is 120 days. Senescent or deformed RBCs are removed by macrophages in the spleen, liver, and bone marrow.

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Overview

Definition and description

Erythrocytes, also called red blood cells (RBCs), are terminally differentiated structures lacking nuclei but filled with oxygen-carrying hemoglobin. Erythrocytes are the most abundant cells in the blood.

  • Diameter: 7.5 μm
  • Biconcave shape:
    • Gives RBCs high surface-to-volume ratio 
    • Sets up most hemoglobin within a short distance from the cell surface, facilitating efficient oxygen transport 
  • Life span: 120 days

Structure

  • Flexible biconcave structure: 
    • Easily bends, permitting passage through small capillaries
    • Membrane proteins, including spectrin and ankyrin, stabilize the membrane to keep the shape and elasticity of RBCs.
  • Components:
    • No nuclei (without nuclei, defective proteins cannot be replaced)
    • Without most organelles 
    • During erythropoiesis, which takes place in the red bone marrow, precursors lose nuclei and organelles prior to release into circulation.
  • Senescent or deformed RBCs are removed by macrophages of the liver, spleen, and bone marrow.
  • Processing of components after degradation:
    • Globin (from hemoglobin): broken into amino acids and reused by the bone marrow for new RBCs
    • Iron: stored in liver or spleen or reused for new RBCs in the bone marrow
    • Nonheme iron: become bilirubin, biliverdin
Electron micrograph of blood cells

Scanning electron micrograph of a blood cell:
Left to right: human RBC, thrombocyte (platelet), and leukocyte

Image: “Electron micrograph of blood cells” by Electron Microscopy Facility at The National Cancer Institute at Frederick. License: Public Domain

Erythropoiesis

RBC production

  • Hematopoiesis:
    • 1st to 2nd month in utero: mesoderm of the yolk sac
    • By the 2nd month, hematopoiesis moves to the liver (and spleen).
    • By the 5th month, hematopoiesis occurs in the bone marrow and the bone marrow becomes the predominant source of blood cells.
  • As with other blood cells, erythropoiesis starts with multipotent hematopoietic stem cells (HSCs).
  • HSCs → multipotent progenitor cells (MPPs) → common myeloid progenitor → burst-forming unit erythroid (BFU-E) → erythrocyte maturation 
Bone marrow hematopoiesis

Bone-marrow hematopoiesis: proliferation and differentiation of the formed elements of blood.
CFU-GEMM: colony-forming unit–granulocyte, erythrocyte, monocyte, megakaryocyte
CFU-GM: colony-forming unit–granulocyte-macrophage
GM-CSF: granulocyte-macrophage colony-stimulating factor
M-CSF: macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
NK: natural killer
TPO: thrombopoietin

Image by Lecturio. License: CC BY-NC-SA 4.0

Stages of erythrocyte differentiation

  1. Proerythroblast:
    • Large, central, pale-staining nucleus with 1–2 large nucleoli
    • Polyribosomes (which provide mild basophilia) in the cytoplasm synthesize hemoglobin.
    • 14–20 μm in diameter
  2. Basophilic erythroblast: 
    • Deep blue (more intense basophilia), smaller cell than proerythroblast
    • Smaller nuclei and patchy chromatin
    • 13–16 μm in diameter
  3. Polychromatophilic erythroblast:
    • Mix of staining affinities: basophilic (from polyribosomes) and acidophilic (from increasing hemoglobin)
    • Nuclei with checkerboard chromatin
    • 12–15 μm in diameter
  4.  Orthochromatic erythroblast (normoblast): 
    • Acidophilic cytoplasm, trace basophilia
    • Small eccentric nuclei with condensed chromatin → ends with extrusion of degenerated or pyknotic nuclei
    • 8–10 μm in diameter
  5. Reticulocyte:
    • Almost similar to mature RBC
    • Difficult to identify without supravital stain
    • If stained with brilliant cresyl blue, residual polyribosomes create a blue-staining cytoplasmic precipitate. 
    • Maturation to erythrocyte occurs in 24–48 hours.
    • Enzymatic digestion or expulsion of organelles 
  6. Mature RBC: 
    • Without nuclei
    • With biconcave shape

Regulation

Table: Regulation of erythropoiesis
Cytokines and growth factorsActivitiesSource
SCFStimulates all hematopoietic progenitor cellsBone marrow stromal cells
GM-CSFStimulates myeloid progenitor cellsEndothelial cells, T cells
EPOStimulates erythropoiesis, including differentiationKidney, liver
IL-3Mitogen for all granulocyte and megakaryocyte/erythrocyte progenitor cellsT helper cells
EPO: erythropoietin
GM-CSF: granulocyte macrophage colony-stimulating factor
SCF: stem cell factor

Other factors:

  • Iron
  • Vitamin B12
  • Intrinsic factor
  • Folic acid
  • Oxygen level

Clinical Relevance

  • Anemia: decrease in total number of RBCs, hemoglobin, or circulating RBC mass. Anemia is usually reflected in decreased hemoglobin and hematocrit, which can arise from reduced hematopoiesis, hemolysis, or blood loss.
  • Hemolytic anemia: anemia due to destruction or premature clearance of RBCs. Hemolytic anemia can be characterized on the basis of increased clearance by the spleen (extravascular hemolysis) or damage caused by a narrowed vascular lumen (intravascular hemolysis). Splenic clearance (extravascular hemolysis) can be due to intrinsic abnormalities of the RBC (membrane, enzyme, hemoglobin) or extrinsic coating by the immune system (e.g. ABO incompatibility).
  • Thalassemia: hereditary cause of microcytic, hypochromic anemia. Thalassemia is a deficiency in either the alpha (⍺) or beta (𝛽) globin chain that results in a hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present. The consequent hemolytic anemia results in severe systemic symptoms, rendering more severely affected patients transfusion-dependent.
  • Megaloblastic anemia: arises due to impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis. Megaloblastic anemia is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies, which can be due to low dietary intake, underlying malabsorptive conditions and medications. Clinical presentation includes anemic and GI symptoms with neurologic manifestations more commonly seen in vitamin B12 deficiency. 
  • Aplastic anemia (AA): rare life-threatening condition characterized by pancytopenia and hypocellularity of the bone marrow, reflecting damage to the hematopoietic stem cells (HSCs). Most cases of AA are acquired and caused by autoimmune damage to HSCs. Known causes of acquired AAs include medications and chemicals, high doses of whole-body radiation, viral infections, immune diseases, and pregnancy. Inherited or constitutional syndromes associated with AA include Fanconi anemia, dyskeratosis congenita, and Down syndrome.

References

  1. Hattangadi, S. M., et al. (2011). From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 118:6258–6268. https://doi.org/10.1182/blood-2011-07-356006 
  2. Mohandas, N. (2021). Structure and composition of the erythrocyte. In Kaushansky, K., et al. (Eds.), Williams Hematology, 10th ed.
  3. Mescher A.L. (Ed.). (2021). Blood. In Mescher A.L. (Ed.), Junqueira’s Basic Histology Text and Atlas (16th ed.) https://accessmedicine.mhmedical.com/content.aspx?bookid=3047&sectionid=255121436
  4. Paulsen D.F. (Ed.). (2010). Hematopoiesis. Chapter 13 of Histology & Cell Biology: Examination & Board Review, 5th ed. https://accessmedicine.mhmedical.com/content.aspx?bookid=563&sectionid=42045308
  5. Singh, V.K., et al. (2014). Manufacturing blood ex vivo: a futuristic approach to deal with the supply and safety concerns. Frontiers in Cell and Developmental Biology. https://www.frontiersin.org/article/10.3389/fcell.2014.00026 
  6. Sposi, N. (2015). Interaction between erythropoiesis and iron metabolism in human β-thalassemia—recent advances and new therapeutic approaches. In Munshi, A., Ed., Inherited Hemoglobin Disorders. https://doi.org/10.5772/61716

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