Erythropoiesis

Erythropoiesis

Overview Sites Process Changes Stages Factors Maturation Hemoglobin

1 Erythropoiesis and Hemopoiesis

Erythropoiesis

Process of origin, development and maturation of erythrocytes (RBCs).

Hemopoiesis

Process of origin, development and maturation of all blood cells.

2 Sites of Erythropoiesis

I. In Fetal Life

In fetal life, erythropoiesis occurs at different sites in different periods.
1. Mesoblastic Stage
  • During the first 2 or 3 months (first trimester) of intrauterine life:
  • RBCs are produced from mesenchymal cells of yolk sac.
2. Hepatic Stage
  • During the next 3 months (second trimester) of intrauterine life:
  • RBCs are mainly produced from liver.
  • Some RBCs are produced from spleen.
3. Myeloid Stage
  • During the last 3 months (third trimester) of intrauterine life:
  • RBCs are produced from red bone marrow and liver.

II. In Newborn Babies and Children

In newborn babies and growing children:
  • RBCs are produced only from red bone marrow.

III. In Adults

1. Up to the age of 20 years

RBCs are produced from red bone marrow of all bones.

2. After the age of 20 years

RBCs are produced from membranous bones and ends of long bones.

3 Process of Erythropoiesis

Stem Cells

In bone marrow, RBCs develop from hematopoietic stem cells.
  • These cells are called uncommitted pluripotent hematopoietic stem cells (PHSCs).
  • PHSCs are designed to form a particular type of blood cell → they are called committed PHSCs.

Two Types of Committed PHSCs

1. Lymphoid Stem Cells (LSC)

Give rise to:

  • Lymphocytes
  • Natural killer (NK) cells
2. Colony-forming Blastocytes
  • Give rise to blood cells other than lymphocytes.
  • When grown in cultures, blastocytes form colonies → hence the name colony-forming blastocytes.

Different Units of Colony-Forming Cells

1. Colony-forming unit-erythrocytes (CFU-E)

RBCs develop from these.

2. Colony-forming unit-granulocytes/monocytes (CFU-GM)

Granulocytes develop from these:

  • Neutrophils
  • Basophils
  • Eosinophils

Monocytes also develop from these.

3. Colony-forming unit-megakaryocytes (CFU-M)

Platelets develop from these.

Developmental sequence:
  • Uncommitted pluripotent hematopoietic stem cell → committed pluripotent hematopoietic stem cell
  • Colony-forming blastocyte → CFU-M → megakaryocyte → platelet
  • Colony-forming blastocyte → CFU-E → RBC
  • Colony-forming blastocyte → CFU-GM → granulocytes and monocyte
  • Granulocytes:
    • Neutrophil
    • Basophil
    • Eosinophil
  • Lymphoid stem cell → lymphocyte.

4 Changes During Erythropoiesis

When cells of CFU-E pass through different stages and finally become matured RBCs, four important changes are noticed:

  1. Diameter of cell is reduced to 7.2 μm from 25 μm.
  2. Disappearance of:
    • Nucleoli
    • Nucleus
  3. Appearance of hemoglobin.
  4. Change in staining properties of cytoplasm.

5 Stages of Erythropoiesis

1. Proerythroblast or Pronormoblast
  • Large in size.
  • Diameter → about 20 μm.
  • Has a large nucleus.
  • Has 2 or more nucleoli.
  • Chromatin network is present.
  • Hemoglobin is absent.
  • Cytoplasm is basophilic in nature.
  • Proerythroblast multiplies several times and finally forms the next stage called early normoblast.
2. Early Normoblast
  • Smaller than proerythroblast.
  • Diameter → about 15 μm.
  • Nucleoli disappear from nucleus.
  • Condensation of chromatin network occurs.
  • Condensed chromatin becomes dense.
  • Cytoplasm is basophilic.
  • Therefore, this cell is also called basophilic erythroblast.
  • Develops into the next stage → intermediate normoblast.
3. Intermediate Normoblast
  • Smaller than early normoblast.
  • Diameter → 10–12 μm.
  • Nucleus is still present.
  • Chromatin network shows further condensation.
  • Appearance of this stage is marked by the appearance of hemoglobin.
  • Because of the presence of a small quantity of acidic hemoglobin:
    • Basophilic cytoplasm becomes polychromatic.
    • It stains both acidic and basic dyes.
  • Therefore, this cell is called:
    • Polychromophilic erythroblast
    • Polychromatic erythroblast
  • Develops into the next stage → late normoblast.
4. Late Normoblast
  • Diameter of cell decreases further to about 8–10 μm.
  • Nucleus becomes very small.
  • Chromatin network becomes very much condensed.
  • Nucleus is now called ink-spot nucleus.
  • Quantity of hemoglobin increases.
  • Cytoplasm becomes almost acidophilic.
  • Therefore, the cell is called orthochromatic erythroblast.
At the end of late normoblastic stage:
  • Nucleus disintegrates by a process called pyknosis.
  • Final remnant of the nucleus is extruded from the cell.
  • Late normoblast develops into the next stage → reticulocyte.
5. Reticulocyte
  • Reticulocyte is slightly larger than matured RBC.
  • It is otherwise known as immature RBC.
  • Reticulocyte is called a reticulocyte because a reticular network or reticulum formed from disintegrated organelles is present in the cytoplasm.
  • In newborn babies:
    • Reticulocyte count → 2–6% of RBCs.
    • This means 2–6 reticulocytes for every 100 RBCs.
  • Reticulocyte count decreases during the 1st week after birth.
  • Later, reticulocyte count remains constant at or below 1%.
  • Number of reticulocytes increases whenever erythropoietic activity increases.
  • Reticulocyte is basophilic because of the presence of disintegrated:
    • Golgi apparatus
    • Mitochondria
    • Other organelles of cytoplasm.
  • During this stage, cells enter the blood capillaries through the capillary membrane from the site of production by diapedesis.
6. Matured Erythrocyte
  • Size of the cell decreases to a diameter of 7.2 μm.
  • Reticular network disappears.
  • Cell becomes mature.
  • RBC has:
    • Biconcave shape
    • Hemoglobin
    • No nucleus.
  • It requires 7 days for the proerythroblast to become a fully developed and matured RBC.

Changes During Erythropoiesis

Stage Diameter Nucleus Staining property Important event
1. Proerythroblast 20 μm Has 2 or more nucleoli and chromatin network Basophilic Synthesis of hemoglobin starts
2. Early normoblast 15 μm Dense chromatin network Basophilic Nucleoli disappear
3. Intermediate normoblast 10–12 μm Further condensation of chromatin network Polychromophilic / polychromatic Hemoglobin starts appearing
4. Late normoblast 8–10 μm Small with very much condensed chromatin; ink-spot nucleus Acidophilic Nucleus disappears by pyknosis
5. Reticulocyte 7–7.5 μm Absent Basophilic Reticulum is formed; cell enters capillary from site of production
6. Matured RBC 7.2 μm Absent Acidophilic Reticulum disappears; cell attains biconcavity
Stages of blood-cell development:
  • CFU-E → Proerythrocyte → Early normoblast → Intermediate normoblast → Late normoblast → Reticulocyte → Erythrocyte.
  • CFU-M → Megakaryocyte → Platelets.
  • CFU-GM → Myeloblast → Premyelocyte →
    • Neutrophil myelocyte → Neutrophil metamyelocyte → Neutrophil
    • Eosinophil myelocyte → Eosinophil metamyelocyte → Eosinophil
    • Basophil myelocyte → Basophil metamyelocyte → Basophil
  • CFU-GM → Monoblast → Premonocyte → Monocyte.
  • Lymphoid stem cell → Lymphoblast → Lymphocyte.

6 Factors Necessary for Erythropoiesis

Factors necessary for development and maturation of erythrocytes are classified into 3 categories:

1. Stimulating factors
2. Maturation factors
3. Factors necessary for hemoglobin formation

I. Stimulating Factors

1. Hypoxia
  • Hypoxia → decreased availability of oxygen to tissues.
  • Hypoxia is the most important stimulating factor for erythropoiesis.
  • It stimulates erythropoiesis by inducing secretion of erythropoietin from kidney.
  • Hypoxia inducible factor senses the reactions of cells to hypoxia and, in turn, increases erythropoietin production.
2. Erythropoietin
  • Erythropoietin is a hormone secreted by peritubular capillaries in the kidney.
  • A small quantity is also secreted from the liver.
  • Hypoxia is the stimulant for secretion of erythropoietin.
Erythropoietin promotes:
  1. Production of proerythroblasts from CFU-E of bone marrow.
  2. Development of proerythroblasts into matured RBCs through several stages.
  3. Release of matured erythrocytes into blood.

Some reticulocytes are also released along with matured RBCs.

3. Thyroxine
  • Thyroxine is a general metabolic hormone.
  • It accelerates the process of erythropoiesis at many levels.
4. Role of Sex Hormones
  • Testosterone has mild erythropoietic action after puberty.
  • Action of estrogen on erythropoiesis is not clear.
  • In animals, estrogen suppresses erythropoiesis.
5. Hematopoietic Growth Factors

Hematopoietic growth factors or growth inducers are:

  • Interleukin-3
  • Interleukin-6
  • Interleukin-11
  • Stem cell factor (steel factor)

Hematopoietic growth factors induce proliferation of PHSCs.

6. Vitamins
  • Vitamins B₃, B₆, C, D and E are necessary for erythropoiesis.
  • Deficiency of these vitamins causes anemia.

7 Maturation Factors

Vitamin B₁₂, intrinsic factor and folic acid are necessary for maturation of RBCs.
1. Vitamin B₁₂ (Cyanocobalamin)

Vitamin B₁₂ is essential for:

  • Synthesis of DNA
  • Cell division
  • Maturation in RBCs
  • It is also called extrinsic factor because it is obtained mostly from diet.
  • It is also produced in the large intestine by intestinal flora.
  • It is absorbed from the small intestine in the presence of intrinsic factor of Castle.
  • Vitamin B₁₂ is stored mostly in:
    • Liver
    • Small quantity in muscle.
Deficiency of vitamin B₁₂

Deficiency of vitamin B₁₂ causes pernicious anemia (macrocytic anemia).

In pernicious anemia:

  • Cells remain larger.
  • Cell membrane is fragile and weak.
2. Intrinsic Factor of Castle
  • Intrinsic factor is produced in gastric mucosa by the parietal cells of gastric glands.
  • It is essential for absorption of vitamin B₁₂ from intestine.
  • Absence of intrinsic factor also leads to pernicious anemia because of failure of vitamin B₁₂ absorption.

Deficiency of intrinsic factor occurs in conditions like:

  • Severe gastritis
  • Ulcer
  • Gastrectomy
3. Folic Acid
  • Folic acid is essential for the synthesis of DNA.
  • Deficiency of folic acid decreases DNA synthesis.
  • Failure of DNA synthesis leads to megaloblastic anemia.

8 Factors Necessary for Hemoglobin Formation

1. First-class proteins and amino acids of high biological value

Required for formation of globin.

2. Iron

Necessary for formation of heme part of hemoglobin.

3. Copper

Helps absorption of iron from GI tract.

4. Cobalt and nickel

Help utilization of iron during hemoglobin synthesis.

5. Vitamins C, B₂, B₃ and B₆

Essential for hemoglobin synthesis.

9 Factors Necessary for Erythropoiesis — Classification

Stimulating factors Maturation factors Factors necessary for hemoglobin synthesis
1. Hypoxia 1. Vitamin B₁₂ 1. First-class proteins and amino acids
2. Erythropoietin 2. Intrinsic factor 2. Iron
3. Thyroxine 3. Folic acid 3. Copper
4. Hematopoietic growth factors 4. Cobalt and nickel
5. Vitamins B₃, B₆, C, D and E 5. Vitamins C, B₂, B₃ and B₆
Erythropoiesis