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Kuliah Patologi Klinik

Rabu, 19 September 2012

Blok 234
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.
2.

Essential Hematology. AV Hoffbrand, JE


Pettit, PAH Moss. 4th ed.
Denise M Harmening. Hematology and
Hemostasis.

AGE
Fetus: 0-2 months

SITE
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+, CD38Appearance ~ 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

Proerythroblast

Intermediate

Polychromatophilic
erythroblast
Basophilic
erythroblast

Late

Reticulocyte

Orthochromatic
erythroblast
(normoblast)

Erythrocyte

Proerythroblast
(pronormoblast)

active rRNA and ribosome synthesis (nucleoli visible)


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

Basophilic
erythroblast

rRNA synthesis largely complete (no nucleoli)


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

Polychromatophilic
erythroblast

protein synthesis mostly complete (less basophilia)


gene expression minimal (more heterochromatin)

Orthochromatic
erythroblast
(normoblast)

protein synthesis complete (no or little basophilia)


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

Reticulocyte

nucleus extruded, small cell size, enters peripheral


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
(do not identify
in lab)

active rRNA and ribosome synthesis (nucleoli visible),


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

Promyelocyte

active rRNA and ribosome synthesis (nucleoli present),


secretory pathway active (1 granules synthesized),
active protein synthesis in cytoplasm (basophilia), gene
expression in nucleus (little heterochromatin)

Myelocyte

secretory pathway active (2 granules synthesized and


Golgi visible), active protein synthesis (basophilia), gene
expression in nucleus (little heterochromatin)

Metamyelocyte

1 and 2 granules (color of 2 = mature granulocyte),


Golgi visible, protein synthesis (some basophilia), some
genes silenced (some heterochromatin), non-mitotic

Band form

1 and 2 granules, protein synthesis (some basophilia),


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
cells:
adipocytes
Fibroblast
Reticulum
cella
Endothelial

secrete

Extracellular
molecules:
Collagen
Glycoprotein
(fibronectin,
thrombospondin)
Glycosaminoglycans
(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

HGF

Stromal cell

IL-1, TNF

Pluripotential stem cell

Stem cell factor (SCF), Flt ligand (Flt-L)

Multipotential progenitor cell

IL-3, GM-CSF, IL-6, G-CSF, thrombopoietin

Committed progenitor cell

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