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HEMATOPOIESIS
dr Sri Lestari Sulistyo Rini, MSc
Hematopoiesis
• Hematopoiesis (hemopoiesis):
blood cell formation
– Occurs in red bone marrow of axial skeleton,
girdles and proximal epiphyses of humerus and
femur
Hematopoiesis
• Hemocytoblasts (hematopoietic stem cells)
– Give rise to all formed elements
– Hormones and growth factors push the cell
toward a specific pathway of blood cell
development
• New blood cells enter blood sinusoids
Hematopoiesis:
• Stem cells in bone marrow
• proliferate
• differentiate
• mature
• myeloid vs. lymphoid
• Stromal cells secrete growth factors
• Cytokines signal via membrane receptors
Bone marrow
• Bone marrow stromal cells secrete growth factors
• Hematopoietc stem cells respond
Stem cells
Hemocytoblast
Lymphoid stem cell
Myeloid stem cell
Committed
cells
Myeloblast
Developmental Promyelocyte
pathway
Myeloblast
Myeloblast
Monoblast
Lymphoblast
Promyelocyte Promyelocyte Promonocyte
Eosinophilic Basophilic
myelocyte
myelocyte
Neutrophilic
myelocyte
Eosinophilic Basophilic
band cells
band cells
Neutrophilic
band cells
Monocytes
Eosinophils Basophils Neutrophils
(a)
(b)
(c)
(d)
Granular leukocytes
Prolymphocyte
Lymphocytes
(e)
Agranular leukocytes
Some become
Some
become
Blood Cell Production
Hematopoiesis involves cytokine signaling
Growth factors signal through membrane receptors:
• Ligand causes receptors to aggregate
• Activates JAK (kinases) by phosphorylation (cytoplasmic
RTK)
•JAK phophorylates cytokine receptor on Tyr
Hematopoiesis involves cytokine
signaling
• Other signaling molecules bind, including STAT
(signal transducer and activator of transcription) →
nucleus transcription
• Also RAS/Raf/MAP kinase activated
• Overactive signal → cancer
• Transient signal:
SOCS silences
Normal Marrow Composition
unidentified or disintegrated cells
erythroid precursors
10%
Lymphocytes, monocytes
20%
10%
60%
granulocytes & precursors
Hematopoietic Growth Factors
(SCF, IL-6, GM-CSF, etc.)
• glycoprotein hormones
• secreted by
– bone marrow stromal cells
– T-cells monocytes
• regulate division and differentiation of
hematopoietic cells
• responsible for basal hematopoiesis and
maintaining blood counts in normal ranges
• greatly increased secretion in response to infection
Erythropoiesis
• erythropoietin-independent stage:
– GM-CSF
– SCF
marrow stromal cells
IL-3 (activated T-cells)
• erythropoietin-dependent stage:
– erythropoietin
hypoxia(liver, kidney)
Granulopoiesis
• early phase:
•
•
•
•
GM-CSF
SCF
Neutropoiesis:
G-CSF
Monopoiesis:
Eosinopoiesis: M-CSF
IL-5 IL-3
Basopoiesis,Mastpoiesis:
IL-3
GM-CSF
SCF
IL-3
Megakaryopoiesis
IL-3
•
SCF
IL-6
GM-CSF
may also play a role
Lymphopoiesis
• B-cells:
– initial stage:
IL-7 SCF
– later stage:
Fcgand
rec
IL-4 IL-6
– final proliferation
Ab secretion:
• T-cells:
•
CD8 cells:
•
CD4 cells:
IL-6
IL-2
Ag
TCR/CD3
CD28
GM-CSF
Hematopoietic Growth Factors
(IL-6, GM-CSF, SCF, etc.)
• Bacterial & viral products
T-cell
•
GM-CSF
IL-3
IL-1
monocyte
TNFa
G-CSF
M-CSF
IL-6
Fibroblast
Endothelial cell
GM-CSF
G-CSF
Hematopoietic Microenvironment
Stromal cells:
fibroblasts
endothelial cells
adipocytes
Growth Factors
Basal Hematopoiesis
SCF
IL-6
GM-CSF
G-CSF
SCF: stem cell factor
GM-CSF: granulocyte-macrophage colony-stimulating factor
G-CSF: granulocyte colony-stimulating factor
Antigen-amplified hematopoiesis
IL-1
TNFa
Ag
IL-1
Ag
TNFa
IL-3
GM-CSF
IL-4
SCF
IL-6
GM-CSF
G-CSF
Erythropoiesis
• Erythropoiesis: red blood cell production
– A hemocytoblast is transformed into a
proerythroblast
– Proerythroblasts develop into early erythroblasts
Erythropoiesis
– Phases in development
1. Ribosome synthesis
2. Hemoglobin accumulation
3. Ejection of the nucleus and formation of reticulocytes
– Reticulocytes then become mature erythrocytes
RBC Formation before birth
•
Mesoblastic stage
– Nucleated RBCs - Yolk sac and
Mesothelial layers of the placenta –
3rd week
•
Hepatic stage
• At 6 weeks - Liver form blood cells
– Spleen + lymphoid tissues form blood
cells.
RBC Formation before birth
•
Myeloid stage
• From the third month onwards - the
bone marrow gradually becomes the
principal source of the RBCs
• Last month – Bone marrow exclusively
RBC Formation after birth
• The bone marrow - all bones - 5 years
• Marrow of the long bones (except for the
proximal humerus and tibia)
– No more red blood cells after = age
20 years.
• Most red cells continue to be produced in the
marrow of the membranous bones, such as
– Vertebrae, Sternum, Ribs, and
Ilium.
Relative rates of red blood cell production in the bone marrow
of different bones at different ages.
Bone marrow cells for Erythropoiesis
• Pluripotential hematopoietic stem cell, PHSC
• Committed stem cell that produces erythrocytes is
called Colony-forming unit–erythrocyte, CFU-E
Factors:
– Growth inducers
– Differentiation inducers.
ERYTHROPOIESIS
PHSC
Bone marrow
CFU-E
4-5 days
Proerythroblast
Polychromatophil erythroblast
Orthochromatophil erythroblast
Reticulocyte
Erythrocyte.
Blood 1-2 days.
Erythropoiesis
– Phases in development
1. Ribosome synthesis in early erythroblasts
2. Hemoglobin accumulation in late erythroblasts
and normoblasts
3. Ejection of the nucleus from normoblasts and
formation of reticulocytes
– Reticulocytes then become mature erythrocytes
– 1 -2 % of all circulating erythrocytes
Stem cell
Hemocytoblast
Committed
cell
Developmental pathway
Proerythroblast
Early
Late
erythroblast erythroblast
Phase 1
Ribosome
synthesis
Phase 2
Hemoglobin
accumulation
Phase 3
Ejection of
nucleus
Normoblast
Reticulo- Erythrocyte
cyte
Regulation of Erythropoiesis
• Too few RBCs leads to tissue hypoxia
• Too many RBCs increases blood viscosity
• Balance between RBC production and
destruction depends on
• Hormonal controls : Erythropoietin (EPO)
– Direct stimulus for erythropoiesis
– Released by the kidneys in response to hypoxia
– Adequate supplies of iron, amino acids, and B
vitamins
Hormonal Control of Erythropoiesis
• Effects of EPO
– More rapid maturation of committed bone
marrow cells
– Increased circulating reticulocyte count in 1–
2 days
• Testosterone also enhances EPO production,
resulting in higher RBC counts in males
Hormonal Control of Erythropoiesis
• Causes of hypoxia
– Hemorrhage or increased RBC destruction
reduces RBC numbers
– Insufficient hemoglobin (e.g., iron deficiency)
– Reduced availability of O2 (e.g., high altitudes)
Erythropoietin Mechanism
Start
Normal blood oxygen levels
Increases
O2-carrying
ability of blood
Stimulus: Hypoxia due to
decreased RBC count,
decreased availability of O2
to blood, or increased
tissue demands for O2
Reduces O2
levels in blood
Enhanced
erythropoiesis
increases RBC
count
Erythropoietin
stimulates red
bone marrow
Kidney (and liver to a
smaller extent) releases
erythropoietin
Figure 17.6
Dietary Requirements for Erythropoiesis
• Nutrients—amino acids, lipids, and carbohydrates
• Iron
– Stored in Hb (65%), the liver, spleen, and bone
marrow
– Stored in cells as ferritin and hemosiderin
– Transported loosely bound to the protein
transferrin
• Vitamin B12 and folic acid—necessary for DNA
synthesis for cell division
(a) Normal erythrocyte has normal
hemoglobin amino acid sequence
in the beta chain.
1
2
3
4
5
6
7
146
1
2
3
4
5
6
7
146
(b) Sickled erythrocyte results from
a single amino acid change in the
beta chain of hemoglobin.
Formation & Destruction of RBCs
Leukopoiesis
• Production of WBCs
• Stimulated by chemical messengers from bone
marrow and mature WBCs
– Interleukins (e.g., IL-1, IL-2)
– Colony-stimulating factors (CSFs) named for the
WBC type they stimulate (e.g., granulocyte-CSF
stimulates granulocytes)
• All leukocytes originate from hemocytoblasts
Production of Leukocytes
• Leukopoiesis is hormonally stimulated by two
families of cytokines (hematopoietic factors) –
interleukins and colony-stimulating factors (CSFs)
• Macrophages and T cells are the most important
sources of cytokines
• Many hematopoietic hormones are used clinically
to stimulate bone marrow
Formation of Leukocytes
• All leukocytes originate from hemocytoblasts
– The mother of all blood stem cells
• Hemocytoblasts differentiate into myeloid stem
cells and lymphoid stem cells
– Myeloid stem cells become myeloblasts or
monoblasts
• Granulocytes form from myeloblasts
• Monoblasts enlarge and form monocytes
– Lymphoid stem cells become lymphoblasts
• Lymphoblasts develop into lymphocytes
Platelets
•
•
•
•
Small fragments of megakaryocytes
Formation is regulated by thrombopoietin
Blue-staining outer region, purple granules
Granules contain serotonin, Ca2+, enzymes,
ADP, and platelet-derived growth factor
(PDGF)
Platelets
• Form a temporary platelet plug that helps
seal breaks in blood vessels
• Circulating platelets are kept inactive and
mobile by NO and prostacyclin from
endothelial cells of blood vessels
Stem cell
Developmental pathway
Hemocytoblast
Promegakaryocyte
Megakaryoblast
Megakaryocyte
Platelets
Lifespan of blood cells
• RBC
• platelet
120 days
10 days
• granulocytes circ : 9 hours
•
tissue : days
• lymphocyte
•
circ : variable (hours to years)
tissue : weeks to years
Hematopoietic Response
hypoxia
RBC
infection
granulocyte/monocyte
antigen
lymphocyte
hemorrhage
platelet
TERIMA KASIH