Haematopoetic

Oleh : Neshya R.P

Moderator : dr. Dian Sukma Sp.PK,
M.Biomed
 Introduction
 Mature blood cells have a relatively short
life span, and the population must be
replaced with the progeny of stem cells
produced in the hematopoietic organs.
 In the earliest stages of embryogenesis,
blood cells arise from the yolk sac
mesoderm.
 Later, the liver and spleen serve as
temporary hematopoietic tissues.
 After Birth, the bone marrow becomes an
increasingly important hematopoietic tissue.
Blood cells have limited lifespans, and need to be replaced

with precisely matching numbers

- Hematocytopoiesis

Young replacing cells come, by many divisions and

steps of differentiation, from stem cells

stem
cell

HEMATOPOIESIS
Cell hierarchy (Haemopoiesis
schematic representation)
 HEMATOPOIESIS Subdivisions
Lymphopoiesis Lym

{
PMN

stem Granulopoiesis Eos

cell
Bas

Myelopoiesis Monocytopoiesis Mon

Erythropoiesis RBC

Megakaryopoiesis Pla
Thrombopoiesis
 HEMATOPOIESIS Lineages for Lymphopoiesis
Pluripotent Monocytopoiesis
stem stem cell Granulopoiesis
(Hemocytoblast)
cell Erythropoiesis
Thrombopoiesis

Lymphoblast Monoblast Myeloblast Pro-erythroblast

Megakaryoblast
Basophilic
Pro-Myelocyte erythroblast

Myelocyte Polychromatic
erythroblast
Orthocromatic
Metamylelocyte
erythroblast

Band granulocyte Reticulocyte Megakaryocyte

Lymphocyte RBC Platelets

Monocyte Granulocyte
 FURTHER DIFFERENTIATIONS
Lym Similar precursor produces
Natural killer cells

{
PMN B lymphocytes
become Plasma cells

Granulopoiesis Eos

Bas
Similar precursor
produces Mast cells
Monocyte or a related
Monocytopoiesis Mon precursor gives rise to many
specialized phagocytes &
antigen-presenting cells
Erythropoiesis RBC Macrophages Kupffer cells
Langerhans cells
Megakaryopoiesis Pla Dendritic cells Microglia
Thrombopoiesis Osteoclasts etc
 Sites of Haemopoiesis
• Yolk sac

• Liver and spleen

• Bone marrow
– Gradual replacement of
active (red) marrow by
tissue inactive (fatty)
– Expansion can occur
during increased need for
cell production
 BLOOD IS MADE
IN THE BONE MARROW
• Axial skeleton
• Inner spongy bone
• Bone marrow is in
the holes
• Bone marrow is a
highly organized /
regulated organ

DMM00_B3.ppt
 BONE MARROW: THE
SOURCE OF BLOOD AND OUR
IMMUNE SYSTEM
• All blood cells arise from “mother
” (stem) cells
– Self renewing
– Safe from harm
– Pluripotent
• Blood production is highly
regulated
– Messages from the body (e.g.
erythropoietin from kidney)
– Microenvironments produce
specific cells
Normal bone • Cytokines (SCF, IL3)
marrow • Growth factors (G-CSF)

BAS03_20.ppt
SCHEMATIC OF
HEMATOPOIESIS
B Lymphocyte
Pre-B
T Lymphocyte

Grans / Monos
PSC CFU-
GEMM
Erythrocytes
BFU-E CFU-E

Platelets
Mega
RES03_3.ppt
 Introduction
• Limited Life span of :
• Granulocytes
• Erythrocytes
• Platelets
• Lymphocytes
 Introduction
• Stem cells
• Self renewal
• Plasticity
• Progenitor cells
• Developmentally-restricted cells
• Mature cells
• Mature cell production takes place from the more
developmentally-restricted progenitors
 Stem cells
• Self-renewal
• Normally in G0 phase of cell cycle
• The capacity for self-reproduction is vastly in excess
of that required to maintain cell production for
normal lifetime
• As cells increase in number they differentiate as well
• Multipotentiality
• Capacity to generate cells of all the
lymphohaemopoietic lineages
 Progenitor cells
• Encompasses from immediate progeny of stem
cells to differentiation cells committed to one
lineage

• Progenitor cells become progressively more

restricted in their differentiation and
proliferation capacity
• Late progenitor cells eventually restricted to one lineage
 Regulation of Haemopoiesis

Controlled cell
Controlled cell production
death

• There should be a balance between cell production

and cell death except at the times of requirement
Regulation of Haemopoiesis

Local environmental control

Stromal cell mediated Haemopoiesis

Haemopoietic
Apoptosis growth factors (Humoral regulation)
Interaction of stromal cells, growth
factors and haemopoietic cells
 Haemopoietic growth factors
• GM-CSF
• Granulocyte-Macrophage colony stimulating factor
• M-CSF
• Macrophage colony stimulating factor
• Erythropoietin
• Erythropoiesis stimulating hormone
(These factors have the capacity to stimulate the proliferation of their target
progenitor cells when used as a sole source of stimulation)

• Thrombopoietin
• Stimulates megakaryopoiesis
 Haemopoietic growth factors
• Cytokines
• IL 1 (Interleukin 1)
• IL 3
• IL 4
• IL 5
• IL 6
• IL 9
• IL 11
• TGF-β

• SCF (Stem cell factor, also known as kit-ligand)

Cytokines have no (e.g IL-1) or little (SCF) capacity to stimulate cell
proliferation on their own, but are able to synergise with other cytokines to
recruit nine cells into proliferation
 Lymphoid T Lymphocyte
Progenitor
LPC
Cell
B Lymphocyte
Megakaryocyte
CFU-Meg
PSC CSC Committed Platelets
Stem Cell
Pluripotent
Stem Cell BFU- CFU-
E RBC
E Colony-forming
Myeloid Unit - Erythroid
MPC
Progenitor CFU- Monocyte
Cell M Colony-forming
Unit -Monocyte

CFU-
CFU- G Neutrophil
GM
Colony-forming Unit -
Monocyte.Granulocyte CFU-
Eosinophil
Eo

HEMATOPOIESIS CFU-
Basophil
Mast
Early lineages
 Lymphoid T Lymphocyte
Progenitor
LPC
Cell
B
Megakaryocyte Lymphocyte
CFU-Meg
PSC CSC Committed TPO Platelets
Stem Cell
Pluripotent
Stem Cell SCF BFU- CFU- EPO

* E RBC
IL-1 E
Myeloid
MPC
Progenitor CFU- M-CSF Monocyte

*
Cell M

*
IL-3,
GM-CSF CFU-
* CFU-
G G-CSF Neutrophil

*
GM
Colony-forming Unit -
Monocyte.Granulocyte CFU-
IL-6 Eosinophil
Eo

HEMATOPOIESIS CFU-
IL-3 Basophil
Mast
Growth factors
 Erythropoiesis and
erythrocytes

• Lifespan – 120 days

• Non nucleated
• Biconcave disc
• Production regulated
by Epo
• Needs Fe, B12, folate
& other elements for
development
 Erythropoiesis
• Erythropoiesis, the formation of red blood cells,
is under the control of several cytokines, namely
steel factor, IL-3, IL-9, GM-CSF, and
erythropoietin.
• The process of erythropoiesis, red blood cell
formation, generates 2.5 × 1011 erythrocytes every
day.
• In order to produce such a huge number of cells,
two types of unipotential progenitor cells arise
from the CFU-GEMM (colony-forming units-
granulocyte, erythrocyte, monocyte, megakaryocyte):
the burst-forming units-erythrocyte (BFU-E) and
colony-forming units-erythrocyte (CFU-E)
 ERYTHROPOIESIS
In developing from the stem cell, the RBC has to
undergo the most changes, which can be categorized
into several morphological/stainable stages and into
less easily detected early stages *

stem*
cell RBC
NORMOBLAST
basophilic
polychromatophilic
ERYTHROBLAST orthochromatophilic

-blast is the common suffix for an immature form of a cell

 ERYTHROPOIESIS

stem
cell RBC
NORMOBLAST
basophilic
polychromatophilic
ERYTHROBLAST
orthochromatophilic
polychromatophilic because, in the cell, orange-staining
hemoglobin is accumulating, while the blue ribosomes
necessary for its synthesis are present, but declining
This idea continues in the form of the reticulocyte
which is an RBC released to the blood, but still with a
network of blue ribosomal material persisting
amongst the hemoglobin
 ERYTHROPOIESIS 2
In developing from the stem cell, the RBC has to
undergo the most changes, which can be
categorized into several morphological/stainable
stages and into less easily detected early stages
stem
Pluripotent Stem Cell
cell
PSC Committed Stem Cell

CSC
Used for some Myeloid Progenitor Cell
specialization,
but more for MPC
Burst-forming Unit -
massive cell Erythroid
division, as
conveyed by BFU-E
“burst” ERYTHROBLAST
 Monocytopoiesis
• Electron micrographs of promonocytes disclose a well-developed
Golgi apparatus, abundant RER, and numerous mitochondria.

• The azurophilic granules are lysosomes, about 0.5 μm in diameter.

• Every day, the average adult forms more than 1010 monocytes, most
of which enter the circulation.

• Within a day or two, the newly formed monocytes enter the

connective tissue spaces of the body and differentiate into
macrophages.
 Platelet Formation
• The formation of platelets is under the control
of thrombopoietin, which induces the development
and proliferation of giant cells known as
megakaryoblasts.

• The unipotential platelet progenitor, CFU-Meg,

gives rise to a very large cell, the
megakaryoblast (25 to 40 μm in diameter), whose
single nucleus has several lobes.

• These cells undergo endomitosis, whereby the cell

does not divide; instead, it becomes larger and
the nucleus becomes polyploid, as much as 64 N.
 Platelet Formation
• The bluish cytoplasm accumulates azurophilic
granules. These cells are stimulated to
differentiate and proliferate by thrombopoietin.

• Megakaryoblasts differentiate into

megakaryocytes , which are large cells (40 to 100
μm in diameter), each with a single lobulated
nucleus.

• Electron micrographs of megakaryocytes display a

well-developed Golgi apparatus, numerous
mitochondria, abundant RER, and many lysosomes .
 Platelet Formation
 Megakaryocytes are located next to sinusoids, into
which they protrude their cytoplasmic processes.
These cytoplasmic processes fragment along
complex, narrow invaginations of the plasmalemma,
known as demarcation channels, into clusters of
proplatelets.
 Shortly after the proplatelets are released, they
disperse into individual platelets. Each
megakaryocyte can form several thousand platelets.
 The remaining cytoplasm and nucleus of the
megakaryocyte degenerate and are phagocytosed by
macrophages.
TERIMA KASIH