Structure and Function of Erythropoietic Tissue

Structure and Function of Erythropoietic Tissue
Presentation lecture from:California State University

The RBCs

Erythropoiesis (RBC production)
* Mature erythrocytes are derived from committed erythroid proginator cells through a series of mitotic divisions and maturation phases.
* Erythropoietin, a humoral agent produced

mainly by the kidneys stimulates erythropoiesis by acting on committed stem cells to induce proliferation and differentiation of erythrocytes in the bone marrow.

o Tissue hypoxia (lack of oxygen) is the main stimulus for erythropoietin production.
o Nucleated red cell precursors in the bone marrow are collectively called normoblasts or erythroblasts.
o RBCs that have matured to the non-nucleated stage gain entry to the peripheral blood.
o Once the cells have lost their nuclei, they are called erythrocytes.

o Young erythrocytes that contain residual RNA are called reticulocytes.
o Bone marrow normoblast proliferation and maturation occurs in an orderly and well defined sequence.
+ The process involves a gradual decrease in cell size, condensation and eventual expulsion of the nucleus, and an increase in hemoglobin production.

Basic blood cell maturation

* Nearly all hematopoietic cells mature in the manner shown below. For RBCs the nucleus is eventually extruded and the cytoplasm increase correlates with hemoglobin increase.
o For red cell production to be efficient , 85% or more of the erythroid activity must have a balanced incorporation of heme and globin to form hemoglobin.
+ The immature, nucleated RBC must have an adequate supply of iron‚ as well as normal production of porphyrin and globin polypeptide chains‚ for adequate synthesis of hemoglobin.
+ Folic acid and vitamin B12‚ are also needed in adequate amounts to maintain proliferation and differentiation.
+ Defects may occur at any stage of development and these defects will lead to the death of the cell.

# Normally 1-15% of the RBCs die during maturation.
# Ineffective erythropoiesis occurs when there is a failure to deliver the appropriate number of erythrocytes to the peripheral blood.
o Normoblasts normally spend 4-7 days proliferating and maturing in the bone marrow.
o The stages of maturation from the most immature to the most mature are:

Pronormoblast or rubriblast
Basophilic normoblast or prorubicyte
Polychromatophilic normoblast or rubicyte
Orthochromic normoblast or metarubicyte
Reticulocyte or polychromatophilic erythrocyte
Mature erythrocyte

+ Reticulocytes are released from the bone marrow into the peripheral blood where they mature into erythrocytes , usually within 24 hours.
+ It is rare to see more than 1% reticulocytes in the peripheral smear from an adult , but common in healthy newborns.
# They can be visualized more easily by staining with new methylene blue which allows for visualization of the remnants of the ribosomes on the endoplasmic reticulum.
o Mature RBCs have a lifespan of 100-120 days and senescent RBCs are removed by the spleen.
o 3 areas of RBC structure/metabolism are crucial for normal erythrocyte maturation, survival and function:
+ The RBC membrane
+ Hemoglobin structure and function
+ Cellular energetics

# Defects or problems associated with any of these will result in impaired RBC survival.
# The RBC must be flexible in order to squeeze through the capillaries of the spleen.
* Flexibility is a property of the membrane and the fluidity of the cell’s content.
# Any decrease in flexibility results in a decrease in RBC deformability and a decrease in RBC survival in passage through the spleen.

The RBC membrane
* The RBC membrane is a semi-permeable lipid bilayer supported by a protein cytoskeleton (contains both integral and peripheral proteins).
* Since the mature cells lack enzymes and cellular organelles necessary to synthesize new lipid or protein, extensive damage cannot be repaired and the cell will be culled in the spleen.

* The constituents of the RBC membrane include:
o Phospholipids- exchange between phospholipids in the membrane and the plasma may occur.
+ Since the fatty acid content of the diet and the plasma are correlated, changes in the diet may have an effect on the fatty acid composition of the phospholipids in the RBC membrane which can adversely effect the flexibility of the RBC and may result in an RBC with a decreased survival time.
o Cholesterol- membrane cholesterol exists in free equilibrium with plasma cholesterol.
+ Therefore, an increase in free plasma cholesterol results in an accumulation of cholesterol in the RBC membrane.
# RBCs with increased cholesterol appear distorted and the increased cholesterol results in the formation of target cells, and acanthocytes.
# An increase in the cholesterol to phospholipid ratio results in a cell membrane that is less deformable and therefore, the RBC has a decreased survival time.

Acanthocytes
Target cells
The RBC membrane
RBC membrane structure
Hemoglobin Structure and Function

* Hemoglobin occupies 33% of the RBC volume and 90-95% of the dry weight.
o 65% of the hemoglobin synthesis occurs in the nucleated stages of RBC maturation and 35% during the reticulocyte stage.
o Normal hemoglobin consists of 4 heme groups, which contain a protoporphyrin ring plus iron, and globin, which is a tetramer of 2 pairs of polypeptide chains.
Structure of hemoglobin
Hemoglobin Structure and Function
Summary of hemoglobin synthesis
Structure of heme
Assembly of hemoglobin
How iron levels affect heme synthesis
Siderocyte
Ringed sideroblast
Hemoglobin Structure and Function
Oxy versus deoxy hemoglobin
Right shift in O2 dissociation curve
Left shift in O2 dissociation curve
Comparison of an O2 dissociation curve at normal pH and with acidosis or alkalosis
Cellular Energetics
Heinz bodies (new methylene blue stain)
Erythrocyte kinetics
Erythrocyte destruction
Extravascular destruction of RBCs
Intravascular destruction of RBCs

Structure and Function of Erythropoietic Tissue.ppt