1. dr Sri Lestari Sulistyo Rini, MSc
HEMATOPOIESIS
dr Sri Lestari Sulistyo Rini, MSc

2. Hematopoiesis Hematopoiesis (hemopoiesis): blood cell formation
Occurs in red bone marrow of axial skeleton, girdles and proximal epiphyses of humerus and femur

3. 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

4. Hematopoiesis: Stem cells in bone marrow proliferate differentiate
mature
myeloid vs. lymphoid
Stromal cells secrete growth factors
Cytokines signal via membrane receptors

6. Bone marrow Bone marrow stromal cells secrete growth factors
Hematopoietc stem cells respond

7. Stem cells
Hemocytoblast
Myeloid stem cell
Lymphoid stem cell
Committed
cells
Myeloblast
Myeloblast
Myeloblast
Monoblast
Lymphoblast
Developmental
pathway
Promyelocyte
Promyelocyte
Promyelocyte
Promonocyte
Prolymphocyte
Eosinophilic
myelocyte
Basophilic
myelocyte
Neutrophilic
myelocyte
Eosinophilic
band cells
Basophilic
band cells
Neutrophilic
band cells
Eosinophils
Basophils
Neutrophils
Monocytes
Lymphocytes
(a)
(b)
(c)
(d)
(e)
Agranular leukocytes
Some
become
Granular leukocytes
Some become

8. Blood Cell Production

9. Growth factors signal through membrane receptors:
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

10. 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

12. Normal Marrow Composition
60%
20%
10%
unidentified or disintegrated cells
erythroid precursors
Lymphocytes, monocytes
granulocytes & precursors

13. 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

14. Erythropoiesis erythropoietin-independent stage:
GM-CSF
SCF
erythropoietin-dependent stage:
erythropoietin
marrow stromal cells
IL-3 (activated T-cells)
hypoxia(liver, kidney)

15. Granulopoiesis early phase: Neutropoiesis: Monopoiesis: Eosinopoiesis:
Basopoiesis,Mastpoiesis:
GM-CSF
SCF
IL-3
G-CSF
M-CSF
IL-5
IL-3
GM-CSF
SCF
IL-3

16. Megakaryopoiesis
may also play a role
IL-3
GM-CSF
SCF
IL-6

17. Lymphopoiesis B-cells: T-cells: CD8 cells: initial stage: later stage:
final proliferation and Ab secretion:
T-cells:
CD8 cells:
CD4 cells:
IL-7
SCF
Fcg rec
IL-4
IL-6
GM-CSF
IL-6
IL-2 Ag
TCR/CD3
CD28

18. Hematopoietic Growth Factors (IL-6, GM-CSF, SCF, etc.)
Bacterial & viral products
monocyte
GM-CSF
IL-3
T-cell
IL-1
TNFa
G-CSF
M-CSF
IL-6
GM-CSF
G-CSF
Fibroblast
Endothelial cell

19. Hematopoietic Microenvironment
Stromal cells:
fibroblasts
endothelial cells
adipocytes
Growth Factors

20. 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

21. Antigen-amplified hematopoiesis
TNFa
IL-1
SCF
IL-6
GM-CSF
G-CSF Ag
IL-1
IL-3
GM-CSF
IL-4
TNFa

22. Erythropoiesis Erythropoiesis: red blood cell production
A hemocytoblast is transformed into a proerythroblast
Proerythroblasts develop into early erythroblasts

23. Erythropoiesis Phases in development
Ribosome synthesis
Hemoglobin accumulation
Ejection of the nucleus and formation of reticulocytes
Reticulocytes then become mature erythrocytes

24. 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.

25. 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

26. 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.

27. Relative rates of red blood cell production in the bone marrow of different bones at different ages.

28. 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.

29. Polychromatophil erythroblast Orthochromatophil erythroblast
ERYTHROPOIESIS
PHSC
CFU-E
Proerythroblast
Polychromatophil erythroblast
Orthochromatophil erythroblast
Reticulocyte
Erythrocyte.
Bone marrow
4-5 days
Blood days.

30. Erythropoiesis Phases in development
Ribosome synthesis in early erythroblasts
Hemoglobin accumulation in late erythroblasts and normoblasts
Ejection of the nucleus from normoblasts and formation of reticulocytes
Reticulocytes then become mature erythrocytes
1 -2 % of all circulating erythrocytes

31. Stem cell
Committed
cell
Developmental pathway
Phase 1
Ribosome
synthesis
Phase 2
Hemoglobin
accumulation
Phase 3
Ejection of
nucleus
Proerythro-
blast
Early
erythroblast
Late
erythroblast
Reticulo-
cyte
Erythro-
cyte
Hemocytoblast
Normoblast

32. 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

33. 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

35. 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)

36. Erythropoietin Mechanism
Imbalance
Start
Normal blood oxygen levels
Stimulus: Hypoxia due to decreased RBC count, decreased availability of O2 to blood, or increased tissue demands for O2
Imbalance
Increases O2-carrying ability of blood
Reduces O2 levels in blood
Erythropoietin stimulates red bone marrow
Kidney (and liver to a smaller extent) releases erythropoietin
Enhanced erythropoiesis increases RBC count
Figure 17.6

37. 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

38. (a) Normal erythrocyte has normal
hemoglobin amino acid sequence
in the beta chain. 1 2 3 4 5 6 7
146
(b) Sickled erythrocyte results from
a single amino acid change in the
beta chain of hemoglobin. 1 2 3 4 5 6 7
146

39. Formation & Destruction of RBCs

40. 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

41. 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

42. 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

45. 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)

46. 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

47. Stem cell
Developmental pathway
Hemocyto-
blast
Promegakaryocyte
Megakaryoblast
Megakaryocyte
Platelets

48. Lifespan of blood cells
RBC days
platelet 10 days
granulocytes circ : 9 hours
tissue : days
lymphocyte circ : variable (hours to years)
tissue : weeks to years

49. Hematopoietic Response
hypoxia
RBC
infection
granulocyte/monocyte
antigen
lymphocyte
hemorrhage
platelet

52. TERIMA KASIH