HIS-1

Hematopoeitic System

Alya Amila Fitrie

Lokot Donna Lubis

Department of Histology
Faculty of Medicine
University of Sumatera Utara
Medan 2015
 BLOOD CELLS
Mature blood cells have a finite lifespan

continuously replaced with the progeny

of stem cells, produced in
the hematopoeitic organs.

2
 HEMATOPOIEISIS IN THE FETUS
1st • Islands of hematopoiesis found in yolk sac. The
islands develop from hemangioblasts →
trimester hematopoietic & endothelial cells

2nd • in the liver & then in the spleen

trimester

7th • the bone marrow becomes the primary site of

hematopoiesis, where it remains during
month adulthood.

• In the adult, an approximate volume of 1.7 L of marrow

contains 10 12 hematopoietic cells.
3
STEM CELLS, GROWTH FACTORS &
DIFFERENTIATION
 Hematopoietic
Stem Cells
(HSCs)

Specific,
Remain irreversibly
stem cells differentiated cell
types
5
2 PROCESSES INVOLVED IN FORMATION OF
BLOOD CELLS: (addition)
1. Differentiation:
– The progressive acquisition of the biochemical,
functional, & morphologic characteristics of the
particular cell type
– Occurs at all stages of hematopoiesis

2. Cell proliferation:
– The production of a large number of mature cells from
a single cell committed to one or more differentiation
pathways
– Occurs in the hematopoietic stem cells, progenitor
cells, (except in the megakaryocytic lineage) & in the
precursor cells
6
HEMATOPOIETIC DI€
FFERENTIATION

•The mechanisms that control

whether a HSC self-renews or
di€
fferentiates remain a mystery

•However, many of the important

players in this regulation have been
identified.
7
PLURIPOTENTIAL HEMATOPOIETIC
STEM CELLS
Migrate from the bone marrow to the lymphoid organ,
where they proliferate : lymphocytes

Lymphoid cell

All blood cells arise from a single type of stem cell

in the bone marrow  pluripotential
hematopoietic stem cells
(HSCs)

Myeloid cell
Develop in bone marrow : granulocytes, monocytes,
erythrocytes & megakaryocytes
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 PRECURSOR CELL LINEAGE
Stem cells →Pleuripotential cells
Give rise to all blood cells; divide to renew their own cell population & to form
progenitor cells → beginning of blood cell formation

Progenitor cells → Less potentiality than stem cells

Committed to formation 1 or 2 blood cell lines; high mitotic activity, dividing to
reproduce self & to from precursor cells

Precursor or blast cells

Begin morphologic differentiation; display characteristics of mature blood cells
they will form; not selfrenewing.

Mature blood cells (after several cell divisions of blast

cells) 9
 Hematopoietic Progenitor Cells or Colony-forming
Units (Cfus) (addition)
• Hematopoietic Progenitor Cells or • Bipotent hematopoietic
Colony-forming Units (Cfus) or progenitor cells
Colony Forming Cells (CFC) – CFU-GM generate colonies
characterized by their ability to containing granulocytes &
form colonies containing cells of macrophages
one or more hematopoietic – CFU-E mega generating colonies
lineages → multipotent, tripotent, containing a mixture of
bipotent or unipotent erythroblasts & megakaryocytes

• CFU-GEMM: generate colonies • The unipotent progenitor cells:

containing a mixture of – CFUG generate neutrophil
granulocytes, erythroblasts, granulocytes
macrophages, & megakaryocytes – CFU-eo generate eosinophil
granulocytes,
– CFU-baso generate basophil
• Tripotent hematopoietic granulocytes,
progenitor cells → CFU-E mega – CFU-M generate macrophages
baso generate erythroblasts, – CFU-E generate erythroblasts
megakaryocytes, &basophil – CFU-mega generate
granulocytes megakaryocytes
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RATE OF DIVISION HEMATOPOIETIC CELLS (addition)

• Stem cells divide at a rate only sufficient to maintain their

relatively small population.

• Accelerated cell division rate in progenitor & precursor cells:

– Progenitor cells divide asymmetrically to produce both progenitor
& precursor cells
– Precursor cells produce only cells on the path to differentiation

• Daily production of differentiated, mature cells in human

bone marrow :
– 3 x 109 erythrocytes/kg/day
– 0.85 x 109 granulocytes/kg/day
– in human bone marrow). Whereas.

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DIFFERENTIATION OF PLURIPOTENTIAL CELLS
DURING HEMATOPOEISIS

12
HEMATOPOIETIC GROWTH FACTORS
• Def : Glicoprotein produced in the bone
marrow by endothelial cells, stromal cells,
fibroblast, developing lymphocytes &
macrophage

• Also produced outside the bone marrow

• Act mainly by :
1. Stimulating proliferation of immature cells
2. Supporting the differentiation of maturing cells
3. Extending the life span and enhancing the functions
of mature cells.
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3 MAJOR GROUPS OF HEMATOPOIETIC
GROWTH FACTORS

Colony stimulating
factors (CSF) → to
Erytropoietin &
stimulate committed
Thrombopoietin
precursor cells to grow in
vitro into cell colonies

Cytokines (primarily interleukin):

produced by leukocyte (mainly
lymphocyte) and make paracrine
& autocrine mechanisms
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HEMATOPOEITIC GROWTH FACTORS

15
Hematopoietic cells  distinct pattern of
growth factor receptors as they
differentiate

Ligand + receptor  leads to

A Activation of The final

conformational intracellular induction of cell
change kinases proliferation
16
 BONE MARROW
• A large & complex organ →
Found in medullary canals of
long bones & in cavities of
cancellous bone

• Two types of bone marrow :

1. Red or hematogenous bone
marrow  blood & blood-
forming cells
2. Yellow bone marrow 
adipose cells

• All newborn  red b.m

• Growth : red  yellow b.m. 17

 BONE MARROW (addition)
• Total mass of an adult: • The hematopoietic marrow: (labile
1600 to 3700 g (50% & altering rapidly in response to
fatty marrow:50% many stimuli)
hematopoietically 1. Hematopoiesis (formation & release of
active marrow) various blood cells), mast cells,
osteoclasts, & some endothelial
progenitor cells
• The function of bone 2. Phagocytosis & degradation of
marrow: circulating particulate material such as
1. Hematopoiesis site microorganisms & abnormal or
(hematopoietic senescent red cells and leukocytes
marrow) 3. Antibody production
2. Mesenchymal stem
cells source that can • Marrow mesenchymal stem cells →
differentiate into
other type of cells differentiate into adipocytes,
3. A large store of hepatocytes, osteoblasts &
reserve lipid (fatty osteocytes, chondrocytes, skeletal &
marrow ) cardiac muscle cells, kidney cells &
neural cell lineages
18
The Stroma of Bone Marrow (addition)
• Red bone marrow composed of:
– Stroma (Gr: stroma, bed)
– Hemopoietic cords or islands of cells
– Sinusoidal capillaries

• The stroma consist of:

– A meshwork of specialized fibroblastic cells called reticular or
adventitial cells
– A delicate web of reticular fibers supporting hemopoietic cells &
macrophages

• The matrix of bone marrow also contains collagen type I,

proteoglycans, fibronectin, and laminin, the latter
glycoproteins interacting with integrins to bind cells to the
matrix.
19
2 COMPARTMENTS OF BONE MARROW:
The marrow stromal
compartment
• A framework of adipose cell, fibroblast,
stromal cells, vascular endothelial cells &
blood vessel

The hematopoietic cell

compartment
• Highly vascularized
20
 THE MARROW STROMAL COMPARTMENT
Endothelial cells, fibroblasts & stromal cell  produce
hematopoietic growth factor & cytokine, that regulate the production
of blood

Endothelial cells : forms a barrier between marrow and blood

Adipose cells : provide a local source and synthesize growth factor

Macrophages : remove and phagocytes

Osteoblast & osteoclast : maintain and remodel the cancellous bone

surrounding the marrow tissue.
21
THE HEMATOPOIETIC CELL COMPARTMENT
The hematopoietic stem cells

• Capable of self-renewal

Committed precursor cells

• Responsible for the generation of distinct cell

lineages

Maturing cells

• Resulting from the differentiation of the

committed precursor cell population
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 Red Bone Marrow
Release of mature blood cells
• Releasing factors: e.q. C3,hormone, some bacterial toxins.

Function:
• Production blood cells
• Destruction of worn-out RBC
• Storage of iron derived from the breakdown of Hb.

23
Bone Marrow

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THE PASSAGE OF BLOOD CELLS ACROSS A SINUSOID
CAPILLARY IN RED BONE MARROW

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STRUCTURE OF BONE MARROW

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1. MATURATION OF ERYTHROCYTES
 SUMMARY OF ERYTHROCYTE MATURATION

Hemoglobine concentration 

Nuclear volume  gradually

Chromatin condensation 

Extrussion of pyknotic nucleus

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 ERYTROPOIESIS
• The major regulator of erytropoiesis →
erytropoietin (EPO)

• Erytropoetin → a glicoprotein produced primarily in

the kidney in respon to hypoxia

• In addition to EPO, the formation of RBCs highly

dependent
– iron metabolism
– vitamin folic acid
– vitamin B12.

29
30
31
2. GRANULOPOEISIS
 LEUKOPOIESIS : GRANULOCYTES
• The Granulocyte-Macrophage CFU: A common
precursor cell of Neutrophilic & macrophage cell
lines

• Eosinophil CFU form Eosinophil

• Basophil Cfus form basophil

• The granulocytes (NEUTROPHIL, EOSINOPHIL &

BASOPHIL) → Have a similar pattern of
proliferation, differentiation, maturation & storage
in the BM
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 MATURATION PROCESS OF
GRANULOCYTES

Cytoplasmic Changes Change In Synthetic Activity

Synthesis proteins
that packed in 2 Production of
organelles: proteins that packed
azurophilic & specific in specific granules
granules
34
 DIFFERENTIATION OF GRANULOCYTES

MYELOBLAST

 larger, spherical or ovoid nucleus,

PROMYELOCYTE basophilic cytoplasm but, locally
acidophilic (+) as azurophilic granules.

Specific granules <<, Azurophilic >>,

MYELOCYTE band nucleus

Abundant specific granules,

METAMYELOCYTE Azurophilic’s <<, Lobulated nucleus
except basophilia
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GRANULOPOEISIS

36
STAGES IN THE DEVELOPMENT OF ERYTROCYTES &
GRANULOCYTES

37
 Developing erythrocytes and granulocytes in marrow.
Plastic section of red bone marrow showing mitotic figures (arrows), a plasma cell
(arrowhead), & fairly distinct regions of erythropoiesis and granulopoiesis.
Most immature granulocytes are in the myelocyte stage: their cytoplasm contains
large, dark-stained azurophilic granules and small, less darkly stained
specific granules. 38
X400. Giemsa
Section of red bone marrow with a group of erythropoeitic cells &
a group of neutrophilopoeitic cells 39
KINETICS OF NEUTROPHIL PRODUCTION

40
3. MATURATION OF LYMPHOCYTES &
MONOCYTES
 LYMPHOCYTES
Lymphocytes
progenitor cells
migrate in the bone
marrow

Thymus  full In the bone marrow,

attributes of T lymphocytes differentiate
lymphocytes  B lymphocytes

migrate
T lymphocytes populate
spesific regions of Peripheral lymphoid
peripheral lymphoid organs, B lymphocytes
organs inhabit & multiply in their
own special compartments

42
 Origin of the main types of
lymphocytes

• B lymphocytes & natural killer

lymphocytes formed in the
bone marrow & leave the bone
marrow already mature, to
seed the secondary lymphoid
organs & transit through the
blood, epithelia, & connective
tissues

• Immature CD4– & CD8– T

lymphocyte precursors
transported by the blood
circulation from the bone
marrow to the thymus, where
they complete their maturation
& leave as either CD4+ or CD8+
cells
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 LEUKOPOIESIS : AGRANULOCYTES 
MONOCYTE
• Monocyte : derive from GM-CSU  neutrophil
& macrophage lineage.

• Under the influence of spesific CSF, each

precursors cells establish its own hierarchy.
– G-CSF : Granulocyte precursor cell from GM-CSU 
myeloblast pathway.
– GM-CSF : Monocyte precursor cell from GM-CSU 
monoblast pathway.
44
MONOCYTES
Monocyte :  up to 18
m, basophilic
cytoplasm, large &
slightly indented
nucleus, nucleoli are
evident

45
 Clinical Significance :
Colony Stimulating Factors

G-CSF : a glycoprotein produced by endothelial cells,

fibroblasts & macrophages in different parts of the body
 ↑ neutrophils.
• The synthetic form of G-CSF : filgrastrim or lenograstim.

GM-CSF : a glycoprotein produced by endothelial cells, T

cells, fibroblasts and monocyte  ↑ formation of
neutrophils, eosinophil, basophil, monocyte and
dendritic cells.
• The synthetic form of GM-CSF : sargramostim and molgramostim. 46
 Clinical Significance :
Interleukin
Have relevant function in the formation &
function of type B & T cells

IL3 : stimulate proliferation of hematopoietic

stem cells & acts together w/ other GF.

IL5 : eosinophil progeny

47
4. ORIGIN OF PLATELETS
ORIGIN OF PLATELETS
 15-50 m, large ovoid nucleus, numerous
nucleoli, cytoplasm homogenous and basophilic

Differentiation

 35-150 m, irregularly lobulated nucleus,

coarse chromatine, no visible nucleoli

Fragmentation of the
cytoplasm of mature
megakaryocyte

49
 MEGAKARYOCYTE

A megakaryocyte in a section of red bone marrow. One

nucleus. Granular cytoplasm 50
 Referensi

• Basic Histology, Text and Atlas, 12th

edition, Luis Carlos Junqueira & Jose
Carneiro
• Histology & Cell Biology,Kierszenbaum.
• Essentials of Human Histology, Second
Edition, William J.Krause, 1996.
• Color Atlas of Basic Histology, Second
Edition, Lange, Irwin Berman, 1998.
• Wheather’s Functional Histology, A
Text and Colour Atlas, Fifth Edition,
Barbara Young, et al., 2006

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52
Histology of Blood

dr. Alya Amila Fitrie, M.Kes, Sp.PA

dr. Lokot Donna Lubis

Department of Histology
Faculty of Medicine
University of Sumatera Utara
Medan 2013
 BLOOD

Specialized
connective
tissue

Consisting of
cells & plasma

54
 PLASMA
The fluid component of the blood

Contain salts & organic compound (amino acids,

lipids, vitamins, proteins & hormones)

In the absence of anticoagulant, cellular element +

plasma proteins → clot in the test tube

The fluid portion from above → serum, essentially

fibrinogen-free plasma
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 CELLULAR ELEMENTS
Erythrocyte

Leucocyte
• Granulocyte
• Neutrophil
• Eosinophil
• Basophil
• Agranulocyte
• Lymphocyte
• Monocyte

Platelets : not a cell

56
ERYTHROCYTE / RED BLOOD CELLS (RBCS)
Non-nucleated, Biconcave-shaped cell,  7-8 m,
4-6.106/mm3

Lack organelles. Consist only of a plasma membrane,

its underlying cytoskeleton (→flexible) , Hb &
glycolytic enzymes

Circulate for 120 days, senescent RBCs removed by

phagocytosis or destroyed by hemolysis in the spleen.

Clinical significance : Cytoskeletal & Hb abnormalities,

Erythroblastosis foetalis
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CELL MEMBRANE OF A RBC

58
RBCs & RETICULOCYTES
RBCs replaced in the circulation
by reticulocytes

Reticulocytes complete their Hb

synthesis & maturation 1-2 days
after entering the circulation

Reticulcytes account for 1-2% of

circulating RBCs
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SPLENOMEGALY
Enlargement
of Spleen
Principal
Causes
Thalasemia: Hypochromic, microcystic
eritrocytes, poikilocytosis, target cells
CLINICAL SIGNIFICANCE

63
LEUKOCYTES / WHITE BLOOD CELLS

6000-1000/mm3

Categorized as Granulocytes (primary

& spesific cytoplasmic granules) &
Agranulocytes (primary granules only)

Leukocytes leave the bloodstream

(diapedesis) & enter connective tissue
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 GRANULOCYTES

Neutrophil Eosinophil Basophil

Multilobed nucleus,  12-15 m. Lifespan varies,

can be distinguished by their cytoplasmic granules

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 NEUTROPHIL

Have a lobulated
nucleus, usually 2-
5 lobules

Lifespan 6-7 hours,

60-70% of
may live > 4 days
circulating
in the connective
leukocytes
tissue
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NEUTROPHIL

67
 EOSINOPHIL

Granules : large,
Bilobed nucleus refractile, stain red in
blood smear

First line of defense

May also leave the
2-4% of circulating against parasites &
circulation →
leukocytes participate in triggering
connective tissue
bronchial asthma

68
Eosinophil

69
 BASOPHIL

Granules : large,
Bilobed nucleus,
metachromatic
that obscured by
cytoplasmic
granules
granules

May also leave the Play role in

Only 1% of
circulation → immediate &
circulating
connective tissue, delayed
leukocytes
resemble mast cells hypersensitivity

70
Basophil

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 AGRANULOCYTES

Lymphocytes Monocyte
Round or indented nucleus, contain only
lysosomal-type, primary granules.

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 LYMPHOCYTE

24-44% of circulating Nucleus : round &

leukocytes slightly indented

Cytoplasm: Large lymphocyte Small lymphocyte

basophilic, appearing (3% of all (97% of all
as a thin rim around lymphocytes, 9-12 lymphocytes, 6-8
the nucleus m) m)

73
LYMPHOCYTE

74
LYMPHOCYTE

75
 MONOCYTES

Nucleus : kidney-
3 - 8 %,  9-12 m
shaped or oval

Circulate in blood Connective tissue

Cytoplasmic 12-100 hours, then → macrophage
granules are small enter connective
tissue Bone → osteoclast

76
 PLATELET
Small cytoplasmic fragment derived from the
megakaryocyte

Megakaryocyte → develop cytoplasmic projection →

proplatelets → fragment into platelets

Central region (granulomere) : mitochondria, RER, Golgi

app., granules
Peripher region (hyalumere) : microtubulus &
microfilament → regulate shape & movement
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PLATELET

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SUMMARY

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Thank you… 80