Kuliah Patologi Klinik

Rabu, 19 September 2012

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FK UNSWAGATI

Indriani Silvia
Hematopoiesis

sistem biologi sel stem yang

meliputi interaksi seluler dalam
perkembangannya dan homeostasis
jaringan, siklus turunan sel stem,
dan reaksi transkripsi (pengulangan
siklus) dengan beragam fenotipe
seluler yang spesifik (berdasarkan
tahapannya).
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
2-7 months 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.
 Give rise to the separate cell
lineage
Exact phenotype unkown
immunological testing:
CD34+, CD38-
Appearance ~ small/medium
size lymphocyte
Cell differentiation occurs
from the stem cell down the
erythroid, granulocytic and
other lineages via the
committed hematopoietic
progenitors cells
restricted in their
developmental potential.
 Stem cell has the capability of self-renewal
cellularity remains constant in a normal healthy
steady state.
 1 SC capable of producing + 106 mature
blood cells after 20 cell divisions.
SC capable of responding to hematopoietic
growth factors with increased production
of one or other cell line when the need
arises.
 Kierszenbaum, Fig. 6-16;
See Ross 5th Ed Table 10.4

PPSC
 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
active gene expression (euchromatin in nucleus)
(pronormoblast)
secretory pathway inactive (no cytoplasmic granules)

rRNA synthesis largely complete (no nucleoli)

Basophilic
active protein synthesis in cytoplasm (basophilia)
erythroblast
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 m 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),
secretory pathway active (1 granules synthesized),
Promyelocyte
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
 Suitable environment for
SC growth & dev.
Composed of stromal cells
+ microvascular network.

Stromal Extracellular
cells: molecules:
adipocytes secrete Collagen
Fibroblast Glycoprotein
(fibronectin,
Reticulum
thrombospondin)
cella Glycosaminoglycans
Endothelial (hyaluronic acid &
 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
 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
 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.
 Site of action
Stromal cell
Pluripotential stem cell
Multipotential progenitor cell
Committed progenitor cell
HGF
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*
 Embryonic SC
totipotent generate
all tissues.
Evidence adults SC
(in different organs)
pluripotent.
Bone marrow:
Hematopoietic SC
Mesenchymal SC clinical
application
th/mesenchymal disease
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
 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