ERYTHROPOIESIS

What is Erythropoiesis?
❖ Is the formation of red blood cells
(RBCs) from progenitor hematopoietic
stem cell in bone marrow under
appropriate growth condition
Erythrocytes Production and Maturation:
Origin of Erythropoiesis:
❖ Main sites of adult erythropoiesis are the sternum and iliac crest
❖ Erythropoiesis begins when there is reduction in hemoglobin (Hb)
concentration in circulating blood
❖ The reduction of Hb will lead to changes in tissue O2 tension and
tissues hypoxia especially within the kidney
❖ In response to hypoxia, it secretes a hormone called erythropoietin
(Epo)
▪ Epo induces the primitive PHSC in the BM to differentiate into
→ colony forming unit-Spleen (CFU-S) and → to burst forming
unit-erythroid (BFU-E) and → to committed erythroid cell
linage (CFU-E) and → to differentiate to the rubriblast stage
(the first stage precursor)
Mechanism of Erythropoiesis:
❖ Epo hormone and others HGFs induces the primitive PHSC in BM
differentiate into colony forming unit-Spleen (CFU-S)
❖ CFU-S is committed progenitor cell develop to CFU-Blast (CFU-B)
❖ CFU-B differentiates earlier to form “committed” erythroid
precursor known as burst-forming unit-erythroid (BFU-E)
❖ After hours to a few days, the BFU-E differentiates to the late
erythroid precursor colony forming unit-erythrocyte CFU-E
❖ Epo and other HGFs stimulate of BFU-E and CFU-E to differentiate
into the rubriblast stage (the first stage precursor)
❖ The rubriblast stage is the first of 6 stages in erythropoiesis ending
in the mature erythrocytes
❖ These stages take place in the BM and result in morphology changes
of the erythroid cells
❖ The stages of maturation from the most immature to the most
mature cells as the following:
❖Changes Take Place During Erythropoiesis:
▪ Changes take place in the rubriblast during differentiates from a
primitive stem (nucleated cell) to a mature functional red cells
▪ RBC is a mature functional cell (non-nucleated stage) entry to the
peripheral blood.
▪ Young erythrocytes that contain some residual RNA are called
reticulocytes
▪ Once the reticulocytes cells have lost their nuclei (RNA), they are
called erythrocytes (mature RBCs)
▪ Immature RBC development to mature RBC is characterized
by:
• A decrease in cell size
• A disappearance of nucleus
• An appearance of hemoglobin formation
• Increase in cytoplasm .
❖ Erythrocyte development is characterized by:
▪ Cell size: a decrease in size from rubriblast12-19 microns to a
mature erythrocyte measuring 6-8 microns in diameter.
▪ Increased chromatin clump and gradually shift from active
euchromation to inactive heterochromatin
▪ Nucleoli: disappear by the rubricyte state.
▪ Ratio N:C decreased results in increase in cytoplasm
▪ RNA activity: decreases in cytoplasm resulting in lighter blue
cytoplasm as the cell matures and the pink coming from the
beginning of hemoglobin production
▪ Hemoglobin production: begins at the rubricyte stage and
increases as the cell matures.
• There is a gradual shifting of predominantly blue to pink
cytoplasmic color as the cell matures to an erythrocyte.
• A mature erythrocyte has no blue color in the cytoplasm
▪ Cytoplasm: become pink color due to presence of Hb
production.
▪ Nucleus: A disappearance and removed
▪ Mitochondria activity:
• decreases with a halo around the nucleus in the rubriblast
and prorubricyte
• Perinuclear halo indicates mitochondria and Golgi
apparatus surround the nucleus they are remove.
• These structures do not pick up stain.
▪ From 14 to16 erythrocytes are produced from one
rubriblast
Efficiency of Erythropoiesis
❖The formation and development of mature RBCs is controlled by
growth factors and inhibitors as well as microenvironment of BM.
❖adult human makes approximately 1012 new erythrocytes every day
❖To get >85% of efficient erythropoiesis must have:
▪ Adequate of heme incorporation with globin to form Hb
▪ Adequate supply of iron as well as for normal production of
porphyrin and globin chains‚ for adequate synthesis Hb
▪ Adequate amounts of Folic acid, vitamin B12 and minerals to
maintain proliferation and differentiation
❖Ineffective erythropoiesis occurs when low supply the above things
and in some pathological conditions
❖Rubriblast normally spend 4-7 days proliferating and maturing in the
bone marrow to become normoblast .
Regulations of Erythropoiesis
❖Factors affect and regulate Erythropoiesis:
I. Oxygen supply of tissues: “Tissue hypoxia”: is the most
important regulator factors
II. Available of BFU-E and CFU-E stem cell
III. Hormonal factors:
• Erythropoietin (Epo)
• Growth hormone
• Steroid hormone
• Thyroid hormone
• Androgens
IV. Dietary factors:
• Proteins (amino acids)
• Iron
• Vitamins:
-Vitamin B
12 & Folic Acid
V. Growth Factors:
• Insulin
• IL-1, IL-4, IL-6, IL-7, IL-11,
IL-12, GM-SCF
• Macrophage inflammatory
protein (MIP) and steel
factor (SF)
• Stem Cell Factor (SCF) very
important for growth and
differentiation of BFU-E
VI. State of liver & bone marrow
Regulations of Erythropoiesis conti .
I. Tissue Hypoxia:
▪ Erythropoiesis begins when there is reduction in Hb concentration in
circulating blood
▪ The reduction in Hb will lead to changes in tissue O2 tension within
the kidney. → i.e. Decreased oxygen supply (hypoxia) to kidney
tissues or any body tissues stimulates secretion of Epo hormone
• Hypoxia stimulates kidney to release renal erythropoietic factor
(REF) and also stimulates liver to produce a special type of globulin.
• Both REF & globulin unite in plasma lead to stimulate
formation of Epo in the kidney and liver.
• Then Epo stimulates CFU-S in BM to differentiate and
produce BFU-E and CFU-E.
• Epo accelerates nearly all stages of RBCs formation, i.e. it
stimulates proliferation & differentiation of committed
progenitor stem cells to increase number of mature RBCs
II. Hormonal factors:
1- Erythropoietin (Epo):
▪ The gene for Epo is located on chromosome 7
▪ its the first human hematopoietic growth factor to be identified
▪ Normally, Epo is produced daily at a constant volume to face
request caused by destruction of the 1% of circulating RBC’s
▪ It is a heat stable glycoprotein, with MW= 46,000Kds,
▪ It is production from kidneys 90% and from liver 10%
▪ It is the most important growth factor in erythropoiesis
▪ Epo can cross the placental barrier of the fetus
▪ Blood levels of Epo are inversely related to tissue oxygenation
▪ There is normally an inverse relationship between
haemoglobin concentration and erythropoietin level.
▪ Epo can be measured in plasma & urine
▪ Normal concentration of Epo up to 20 mU/mL
▪ The level of Epo can increase up to 20,000 mU/mL in
response to anemia or arterial hypoxemia
▪ High level of Epo found in many
• Pathological conditions such as: Anemia, Lung diseases,
Hemorrhage, Heart failure and
• physiological in High altitude
▪ Hypoxia induce ( increase in production of Epo ) by
messages transmitted to BM from oxygen sensor in the kidney
▪ Erythropoietin Receptors:
• Epo binds to specific receptors on surface of CFU-S
and BFU-E & CFU-E to increase their number and
stimulate proliferate and differentiation
• They are found with highest number on CFU-E &
pronormoblasts.
• The number of Epo receptors per cell gradually decreases
during erythroid cell differentiation
• Reticulocytes and mature erythrocytes do not contain
Epo receptors
❖Mechanism production of Epo
Epo Regulation of Erythropoiesis