Transcript Bez nadpisu - Masaryk University

Physiology of the bone marrow
• 1. Hemopoiesis as a self-renewal system. Stem
cell of hemopoiesis
• 2. Unipotent (determined) progenitors,
proliferation-differentiation and maturation
compartments. Methods of their study
• 3. Regulation of the hemopoietic system
• 4. Systems analysis of the hemopoietic function
in physiological and pathophysiological
conditions
• 5. Structure and physiology of RBC
1. Hemopoiesis as a self-renewal system.
Stem cell of hemopoiesis
A self-renewal system loses mature (functional) cells
steadily and replaces them continually. Normally it is
composed of three cellular compartements:
- pluripotent stem cells which are capable of
- non declining (steady) autoreproduction
- differentiating into various developmental
lines (pluripotentiality)
- unipotent cells capable of dividing proliferation)
- differentiated functional (postmitotic) cells
unable of division
Blood forming organs represent a typical example of a selfrenewal system (Fig. 1).
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All non-stem populations are transitory. The transit times in
the individual compartements:
Two types of damage:
- loss of mature cells (e.g., bleeding, inflammation)
- damage to the stem cell and precursor compartement
(e.g., radiation, cytotoxic drugs)
Lymphatic organs are totally dependent on the marrow
Fig 2 : Erythropoiesis, the development and maturation of
the red blood cells
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2. Unipotent (determined) progenitors,
proliferation-differentiation and maturation
compartments. Methods of their study
The historically first method of the stem cell detection:
colony forming units spleen (CFU-S)
Fig. 3, Fig. 4: The stages which cannot be differentiated
morphologically are detected by means of shortterm colonies in vitro
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Besides, the stem and precursor cells could be identified
by means of flow cytometry ( numbers of different
cells) and light-activated cell sorting ( preparing of
homogenous cell populations, Fig. 5)
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1. Regulation of the hemopoietic system
Fig. 6: Hemopoietic inductive microenvironment (HIM)
- fibroblast-type “reticulum” cell – granulopoietic islands
- macrophage-type “reticulum” cell – erythroblastic islands
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Cytokines = peptides taking part in the signalling among the
immune and hematopoietic system cells. No hormones
(endocrine). Types:
- Interleukins (Il-1, 2,...etc.)
MF, T cells, stromal cells (HIM) growth
and differentiation of
- lymphocytes
- hematopoetic stem cells (some of them
are known as “colony stimulating
factors”, CSF)
Ils taking part in steady-state hemopoiesis:
- multi-CSF (= Il-3) from helper T-cells
- GM-CSF
- Il-6
- Il-7 (development of B- and T-lymphocytes)
In non-steady-state-conditions: production
of a number of growth factors more specific in
their actions which are usually produced by
activated blood cells or fibroblasts: Il-4 and Il-9
(production of basophils and mast cells), Il-5
(eosinophils), G-CSF, M-CSF, EPO
- Interferons: induced in response to a variety of
agents including viruses, microorganisms and
endotoxins. Upon induction, they circulate to
neighboring cells which they stimulate to make
antiviral proteins
- Lymphokines: Proteins secreted by some helper T
cells after they are primed by contact with an
antigen. Are not antibodies but are mediators of
cellular immunity. They activate various white
blood cells, incl. other lymphocytes. Examples:
interleukin 2, some interferons, migration
inhibition factor (MIF)
- Tumor necrosis factors: have cytotoxic effects on
tumor cells but not on normal cells. TNF is
secreted by macrophages in response to bacterial
infection and other challenges, TNF by helper T
lymphocytes and cytotoxic lymphocytes.
Synergistic with interferons
4. Systems analysis of the hemopoietic function
in physiological and pathophysiological
conditions
The homeostasing of the blood cell production is
regulated by several feedbacks. Their interplay may be
rather complex and can be understood by means of
mathematical modelling only (Fig. 7, 8, 9)
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5. Structure and physiology of RBC
The RBS have lost
- mitochondria, citric acid cycle and oxydative
phosphorylation forming ATP  anaerobic
glycolysis must be the main source of ATP in
them;
- ribosomes  no protein synthesis, detrition of
enzymes etc.
RBC membrane:
Fig. 10: glycophorins can attach lectins =
phytohemagglutinins, viruses and malaria parasites
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Fig. 11a, b: Spectrin and actin  filamentous
network responsible for the biconcave shape of RBC;
ankyrin links spectrin molecules to anion-transport
proteins (“band 3”)
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Hemoglobin
protection against
oxidation (Fig. 12)
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RBC shape and its life span (Fig. 13)
)
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