BONE MARROW AND

HEMATOPOIESIS
DR. NAJEEB LECTURE NOTES
BY FATIMA HAIDER
KGMC

1. HEMATOPOIESIS
o The process of producing blood cells
 i.e., RBCs, WBCs & platelets.
 cells responsible for hematopoiesis – Hematopoietic stem cells.

A. STEM CELLS
o Stem cells  cells that have potential to develop into many different cell types.
 A stem cell can differentiate into muscle cells or brain cells.
o Stem cells, special feature – when stem cells divide – some cells
 Differentiate into a cell type – for instance a nerve cell.
 Some cells divide & maintain their own population,

 Hence stem cells – property of self-renewal.

 Erythroblast for instance – does not have ability of self-renewal –
 It can only differentiate into – erythrocytes & not into erythroblast.

B. HEMATOPOIETIC STEM CELLS

 Hematopoietic stem cells – cells which give rise to different types of blood cells
 First appear in yolk sac, (3rd week).
 Also appear in
 mesoderm of aorta,
 mesoderm of gonads and
 mesoderm of mesonephron.

 Around 3 months of fetal life  Hematopoietic stem cells transfer to

 liver of fetus (mainly)
 spleen
 lymph nodes.
 Around 4th month of fetal life  the stem cells  from liver, spleen and lymph nodes  transfer to
bone marrow.
 Mnemonic – 3 3 4.

C. STEM CELLS IN BONE MARROW

 By the time birth, all hematopoietic activity – occurs in bone marrow.
  Bone marrow is one of the largest organs of body
 size and weight  equal to liver.
 Bone marrow – two types:

a) Red bone marrow – active in hematopoiesis and highly vascular. (Constitutes 50 % in adults)
 In newborn baby, all born marrow – red bone marrow.
 Up to puberty, again – almost all bone marrow – red bone marrow.
 After puberty, hematopoiesis stops in long and peripheral bones.
 Around age 18 or 20, hematopoiesis is limited to axial skeleton and proximal ends of humerus
and femur.
 (axial = central bones  skull, clavicle, sternum, scapula, vertebral column, ribs, pelvis)
b) Yellow bone marrow (also 50 % in adults) – inactive – large number of fat cells and small
number of hematopoietic cells.
 If need of excessive hematopoietic activity,  yellow bone marrow has capacity to re-activate and
convert to red bone marrow.
 For instance, in severe Hemolysis.
 Inactive Bone marrow can increase its activity up to 8 times.

HAIR-ON-END
2. APPEARANCE
HEMATOPOIETIC CELLS PROGENY
SKIP
 Hair-on-end appearance
of skull –a radiologic
characteristic
appearance of skull
which is a characteristic
feature of chronic
hemolysis – when red
bone marrow in skull is
expanding very rapidly
it resorbs resorbs the
bone as bone marrow is
expanding and
occupying space of
bone – usually seen in
patients with
thalassemia and sickle
cell anemia.
A. PLURI-POTENT STEM CELLS
 Hematopoiesis begins with pluri-potent stem cells.
 Toti-potent Stem Cells – Stem cells that can give rise to any to all/ any type of cell in the body
 Zygote is the example of Toti-potent stem cell.
 Pluri-potent stem cells  stem cells that can give rise to many different cell types in the body but
NOT ALL the cell types.
 Pluripotent stem cells  cannot give rise to skin cells  ONLY to different Blood cells.
  pluri-potent stem cells  multipotent stem cells –
 give rise all the different types of blood cells.
 Pluripotent SC differentiate into –

1. Common Lymphoid stem cells

2. Common Myeloid stem cells

I. COMMON LYMPHOID STEM CELLS

 CLSCs  three committed stem cells.
1. Pro-NK stem cells
2. Pro-T stem cells
3. Pro-B stem cells

a. PRO-NK STEM CELLS

 The pro-NK stem cells  develop into NK cells.
 After development move to Secondary Lymphoid organs

b. PRO-T STEM CELLS

 The pro-T stem cells  give rise to Naïve T-lymphocytes.
  T-lymphocytes – do not mature inside bone marrow.
 Immature T cells (aka naïve T cells ) move from bone marrow  thymus for maturation.
 After maturity move to Secondary lymphoid tissue
  spleen tonsils Peyer Patches & lymph nodes.

c. PRO-B STEM CELLS

 Pro B SCs – give rise B cells
 After formation  move to Secondary lymphoid tissue

II. COMMON MYELOID STEM CELLS

Myeloid stem cells divide  two types of committed stem cells:

1. 1st committed stem cell differentiates into

 Colony forming unit (CFU) Erythroid SC / Megakaryoid SC.
2. 2nd committed stem cell differentiates into
 CFU Granulocyte / CFU Monocyte

I. CFU Erythroid Stem Cell / CFU Megakaryoid Stem Cell

 These stem cells after successful differentiation FINALLY give rise to
 Erythroblast
 Megakaryocyte
 Erythroblast & Megakaryocyte  NOT stem cells – CANNOT maintain their population.

 Erythroblast move to peripheral circulation – then convert to Erythrocyte (mature RBC).

 Erythropoietin (EPO) – synthesized
 PCT cells of kidney (mainly)
 Megakaryocyte (within bone marrow)  have larger finger-like processes
 These processes break down into small pieces  small pieces released into blood – these pieces
converts to platelets (thrombocytes)
 Thrombopoietin (TPO) – synthesized by
 PCT cells of kidney
 Liver (mainly)
 moves to red bone marrow and stimulates platelet pathway

II. CFU GRANULOCYTE / CFU MONOCYTE

 These are not Stem cells –cannot maintain their own population.
1. CFU Granulocytes  Myeloblast –
 myeloblast will differentiate into either
 Neutrophil
 Eosinophil
 Basophil
 These three are granulocytes – contain typical granules
  Basophils resemble mast cells.
 Basophils have protein receptors on their cell surface that bind Ig E, an immunoglobulin involved
in parasite defense and allergy.
 Basophils are similar in both function and appearance to mast cells. The difference is that mast cells
are released from bone marrow while basophils are derived from myeloid stem cells.

2. CFU Monocyte  Monoblast  Monocytes

 Monocytes – non granulocytes.
 Does not contain standard granules.
 When monocytes move to an inflamed tissue, it is called macrophage.
 Macrophages of CNS – microglia.
 Macrophages of Liver  Kupfer cells.
 Macrophages of alveoli  Alveolar macrophages.
 Macrophages of spleen and lymph nodes  Dendritic cells.
 Macrophages of Kidney  Mesangial cell.
 Macrophages of Bone  osteoclasts.


 Hematopoiesis Abnormalities

1. APLASTIC ANEMIA
 A condition that occurs when the pluripotent stem cells do not multiply well (i.e., hypo proliferation)
 Manifestation –  number of all blood cells.
 Aplastic anemia carries all –
 Anemia
 Thrombocytopenia
 Leukopenia
 Having these three altogether  pancytopenia

2. LEUKEMIA
 Leukemia – over-proliferation of hematopoietic stem cells.
 Only disturbs the WBCs lineage.

3. STROMAL CELLS
o Bone marrow has a lot of stromal cells
 Stromal cells concentrate growth factors and thereby influence stem cells proliferation
 These GF support the hematopoietic process.

4. ERYTHROPOIETIN
o By PCT of kidney (mainly).
 Chronic renal failure  patient severely deficient in erythropoietin erythropoiesis slows down
 Develops anemia.
 Tx for chronic renal failure  erythropoietin injections

5. HOMING
o Process whereby bone marrow cells including stem cells, progenitor cells and differentiated cells, find
their way into the bone marrow after being injected into the blood stream.

6. HEMANGOBLAST
o Bone marrow stem cells can be induced to produce Hemangoblast.
Hemangoblasts are multipotent precursor cells that can differentiate into both hematopoietic and
endothelial cells.

7. SINUSOID NETWORKS IN BONE MARROW

o Bones are lined by sinusoidal capillaries
 S. capillaries  endothelial cells with

 Large inter-endothelial gaps.

 Gaps in endothelial cells itself
 Basement membrane is not effectively present in these capillaries  discontinuous at many points.
8. INTERSTITIUM OF BONE
o The spaces between sinusoids  interstitium of bone marrow.
stem cells location  in the interstitium.

9. ERYTHROPOIESIS
Erythroblast in the interstitium goes through developmental changes. Their size decrease, the
nucleus condenses and eventually disappears.
Total erythropoiesis process takes about 1 week under strong influence of erythropoietin.
Erythropoietin is produced in endothelial cells of peritubular capillaries of kidneys. Endothelial cells of
peritubular capillaries have the capability to monitor the oxygen in blood. If partial pressure of oxygen is
low, endothelial cells will start synthesizing and releasing erythropoietin which will move to bone
marrow to accelerate erythropoiesis and increased production of RBCs take place thereby increasing
oxygen carrying capacity of blood.
Development of Erythroblasts
Proerythroblasts  Early basophilic normoblast  Intermediate normoblast  late normoblast 
Reticulocyte  mature RBCs
Proerythroblast – large cell with fine chromatin nucleus (euchromatin) with basophilic cytoplasm
(blue) and prominent nucleoli. Whenever cytoplasm is rich in mRNA and ribosomes, the cytoplasm will
be blue-colored.
Early basophilic normoblast – smaller than proerythroblasts with more condensed chromatin and lower
nuclear-cytoplasmic ratios. The cytoplasm is deep blue, and a pale perinuclear halo may be present.
Intermediate normoblast (Polychromatophilic) – nucleus condenses, chromatin lumps and Hb starts
appearing. Known as polychromatophilic due to the two-colored cytoplasm, blue representing basophilic
cytoplasm due to polysomes and red representing Hb.
Late Normoblast (Orthochromatic) - In the late normoblast stage, the chromatin is dark, dense, and
clumped, ready to be extruded. Cytoplasm is like mature red cell, reflecting a high Hb content.
Reticulocyte – The nucleus leaves the cell, and the newly formed cell is called reticulocyte. Normally
reticulocyte percentage in blood is 1-2%
Mature Erythrocyte – Reticulocyte moves to sinusoids network and within 1-2 days, it develops
into mature RBCs.

10. MEGALOBLASTIC ANEMIA

o For nuclear maturation and condensation of erythroblast, B12 and folic acid are required.
 The deficiency of B12 and folic acid leads to uncondensed chromatin network even though
hemoglobin is produced.
 This normoblast keeps producing hemoglobin in abnormally large quantities. This large, abnormally
 developed cell is called megaloblast. Most of these cells are destroyed within bone marrow, due to
which RBC production is slowed down. So total RBCs in blood is reduced and this results in
megaloblastic anemia.
For cytoplasmic maturation of erythroblast, iron is required. Hb cannot be produced without iron.

11. GRANULOPOIESIS
o Myeloblast  Promyelocyte  Myelocytes  Immature Neutrophils  Mature neutrophils

o Granulopoiesis produces 65% of bone marrow cells Erythropoiesis produce 25% of bone marrow cells
Lymphopoiesis produce 10% of bone marrow cells Myeloid-Erythroid ratio  3:1
12. BONE MARROW EXAMINATION
1. Bone marrow aspirations
2. Bone marrow biopsy
o Both tests show whether bone marrow is healthy and making normal amounts of blood cells.
 Bone marrow has a fluid portion and a solid portion.

 Bone marrow aspiration, – withdraw a sample of the fluid portion.

 Bone marrow biopsy– withdraw a sample of the solid portion.

13. AVERAGE LIFE SPAN OF BLOOD CELLS

RBCs – 120 days
Platelets – 7 to 8 days
Neutrophils – 24 to 48 hours (During inflammation, life span may reduce to 6-7 hours)

14. Pearls
Blood cell maturation is stimulated by growth factors