HEMATOPOIESIS

Kuliah Patologi Klinik

Selasa, 1 Oktober 2013

Blok 234
FK UNSWAGATI

Indriani Silvia
Hematopoiesis

sistem biologi sel stem interaksi seluler

dalam perkembangannya
homeostasis jaringan
siklus turunan sel stem
reaksi transkripsi (pengulangan siklus) dengan
beragam fenotipe seluler spesifik
(berdasarkan tahapannya).
Reference Books
1. Essential Hematology. AV Hoffbrand, JE Pettit,
PAH Moss. 4th ed.
2. Denise M Harmening. Hematology and
Hemostasis.
 AGE SITE

Fetus: 0-2 months Yolk sac

Site2-7ofmonths
hematopoiesis
Liver, spleen

5-9 months Bone marrow

Infants Bone marrow, practically all bones

Adults Vertebrae, ribs, sternum, sacrum and

pelvis, proximal ends of femur

• Developing cells situated outside of BM sinuses  mature cells

released into sinus spaces  marrow microcirculation  general
circulation.
•Hematopoiesis starts with pluripotent stem cell
Hal-hal yang mempengaruhi dan
regulasi hematopoieisis
 Sel-sel
trombopoietik &
hematopoietik
 Pluripotent(ial)
Hematopoietic Stem Cell
• Stimulasi sel sesuai jalurnya
• Fenotip tidak diketahui uji
imunologi: CD34+, CD38-
• gambaran~ ukuran limfosit
kecil/medium
• Diferensiasi sel dimulai dari
sel stem, dibagi eritroid,
granulositik dan committed
hematopoietic progenitors
cells.
• Sel stem mampu memperbarui diri sistem
selularitas konstan dalam kondisi “sehat”.
 1 SC produksi + 106 sel darah matur setelah
20 kali pembelahan sel.
 SC mampu merespons faktor
pertumbuhan hematopoietik 1 atau lajur
sel lainnya yg diperlukan untuk membelah.
 Kierszenbaum, Fig. 6-16;
See Ross 5th Ed Table 10.4

PPSC
 Stem Cell Basics

• Stem cell - asymmetric cell division yields cells with different

fates (one is stem cell; one is transient amplifying cell)
• Self-renewal - capacity of stem cell to regenerate itself
• Transient amplifying cells - symmetric cell division yields
daughter cells with same fate (transient amplifying cells)
• Differentiated cells - cells exit cell cycle and differentiate
Pluripotent hematopoietic stem cell (HSC)
Undifferentiated cell producing blood cells of all lineages,
capable of self-renewal

Multipotent HSC
Undifferentiated cell producing cells of multiple lineages,
limited self-renewal (e.g., myeloid SC, lymphoid SC)

Committed progenitor - undifferentiated cell capable of

producing cells of one lineage, colony forming units (CFUs)
(e.g., erythroid CFU, granulocyte-macrophage CFU)
 Early Intermediate Late

Proerythroblast Polychromatophilic Reticulocyte

erythroblast

Basophilic Orthochromatic Erythrocyte

erythroblast erythroblast
(normoblast)
 active rRNA and ribosome synthesis (nucleoli visible)
Proerythroblast
(pronormoblast)
active gene expression (euchromatin in nucleus)
secretory pathway inactive (no cytoplasmic granules)

rRNA synthesis largely complete (no nucleoli)

Basophilic
erythroblast
active protein synthesis in cytoplasm (basophilia)
gene expression in nucleus (some heterochromatin)

Polychromatophilic protein synthesis mostly complete (less basophilia)

erythroblast gene expression minimal (more heterochromatin)

Orthochromatic protein synthesis complete (no or little basophilia)

erythroblast gene expression silenced (condensed chromatin)
(normoblast) no mitosis, nucleus may be off-center

nucleus extruded, small cell size, enters peripheral

Reticulocyte
blood, 1-2% of cells in blood, matures in 1-2 days

Erythrocyte mature, biconcave shape, 7.6 µm diameter

 Band Stage

Kierszenbaum
Fig. 6-20;
See Ross 5th
Ed Table 10.4
1. Promyelocyte 3. Metamyelocyte

2. Myelocyte 4. Band Form

Kierszenbaum, Fig. 6-21
 Myeloblast active rRNA and ribosome synthesis (nucleoli visible),
(do not identify active gene expression (euchromatin in nucleus),
in lab) secretory pathway inactive (no cytoplasmic granules)
active rRNA and ribosome synthesis (nucleoli present),
Promyelocyte secretory pathway active (1° granules synthesized),
active protein synthesis in cytoplasm (basophilia), gene
expression in nucleus (little heterochromatin)
secretory pathway active (2° granules synthesized and
Myelocyte Golgi visible), active protein synthesis (basophilia), gene
expression in nucleus (little heterochromatin)
1° and 2° granules (color of 2° = mature granulocyte),
Metamyelocyte Golgi visible, protein synthesis (some basophilia), some
genes silenced (some heterochromatin), non-mitotic
1° and 2° granules, protein synthesis (some basophilia),
Band form nuclear segmentation continues, some genes silenced
(some heterochromatin), non-mitotic, enters blood
Pluripotent
stem cell

• Lymphoid stem cell gives rise to

T-lymphocyte and B-lymphocyte
lineages
• T-cell maturation - thymus
• B-cell maturation - bone marrow
• Plasma cells - present in marrow,
lymphatic tissue, connective tissue

See Ross 5th Ed Table 10.4

Kierszenbaum,
Fig. 6-14

• Bone marrow cavity - marrow proper and venous sinuses

• Bone marrow cells - stromal cells, adipocytes, endothelial
cells, macrophages, hematopoietic cells
• Blood vessels - nutrient arteries supply marrow cavity
• Stem cells and early precursor cells do not leave marrow
Bone Marrow Stroma
Suitable environment for
SC growth & dev.
Composed of stromal cells
+ microvascular network.

Stromal cells: Extracellular molecules:

• adipocytes • Collagen
• Fibroblast secrete • Glycoprotein (fibronectin,
• Reticulum cella thrombospondin)
• Glycosaminoglycans
• Endothelial cells
(hyaluronic acid &
• Macrophages chondroitin derivates)
• Growth factors  for cell
 FAKTOR YANG MEMPENGARUHI HEMATOPOITIK
Hemopoietic Growth Factors/HGF

• Glycoprotein hormones  regulate proliferation &

differentiation of hematopoietic pluripotent cell
(HPC) & function of mature blood cells.
• Biological effects of HGF mediated through specific
receptors on target cells.
• Act:
– Locally  at the site where they are produce  by cell-
cell contact.
– Circulate in plasma
Hemopoietic Growth Factors
May bind to EC matrix  form niches to which SC &
PHC adhere.
Major sources (except erythropoietin):
T-lymphocytes
Monocytes (& macrophages)
Stromal cells
Erythropoietin  90% synthesized in kidney
Thrombopoietin  largely made in liver
Leukopoiesis also stimulates by endotoxin
General Characteristics of Myeloid and Lymphoid Growth Factors
• Glycoprotein that act at very low concentration
• Act hierarchically
• Usually produced by many cell types
• Usually affect more than 1 cell lineage
• Usually active on stem/progenitor cells and on functional
end cells
• Usually show synergistic or additive interactions with other
growth factors
• Often act on the neoplastic equivalent of a normal cell
• Multiple actions: proliferations, differentiation,
maturation, functional activation, prevention of apoptosis.
Hematopoietic
Growth Factor

Site of action HGF

Stromal cell
Pluripotential stem cell
Multipotential progenitor cell
Committed progenitor cell
IL-1, TNF
Stem cell factor (SCF), Flt ligand (Flt-L)
IL-3, GM-CSF, IL-6, G-CSF, thrombopoietin
G-CSF*, M-CSF, IL-5 (eosinophil-CSF),
erythropoietin, thrombopoietin*
 Stem Cell Plasticity

 Embryonic SC 
totipotent  generate all
tissues.
 Evidence  adults SC (in
different organs) 
pluripotent.
 Bone marrow:
 Hematopoietic SC
 Mesenchymal SC  clinical
application 
th/mesenchymal disease
Growth Factor Receptors
& Signal Transduction
Control hematopoiesis by growth
factors:
• Factors acts on cells expressing the
corresponding receptors.
• Binding of GF to its receptor activates
by JAKs  then phosphorylate STATs
which translocate to the nucleus and
activate transcription of specific
genes
Adhesion Molecules
• Glycoprotein
• Mediate the attachment of marrow precursors,
leukocytes and platelet to various components of the
extracellular matrix to:
– Endothelium
– Other surfaces
– Each other
• On leukocyte  receptors  interact with ligand
• 3 main families: Immunoglobulin, selectins, integrin
Any questions?