Transcript The stem cell

GENERATION OF CELLS OF THE IMMUNE SYSTEM
STEM CELLS
EMBRYONIC STEM CELLS
BONE MARROW DERIVED
STEM CELLS
CD34+ HEMATOPOIETIC
MESENCHYMAL
DECISION OF CELL DIFFERENTIATION
Discovery of stem cells
Till és McCullogh 1960
Spleen of irradiated mouse
Colony forming units (CFU)
MYELOID
FERTILIZED EGG
LYPHOID
Omnipotent
EMBRYONAL STEM CELL
Pluripotent
TISSUE STEM CELL
Multipotent
EARLY MOUSE EMBRYOS
Blastocyst stage of differentiation
4.5 DAY
5.5 DAY
Ectoplacental part
EXTRAEMBRYONAL PARTS
Primitive ectoderm
Inner Cell Mass
ICM
Primitive sheet
Extraembryonal ectoderm
Primitive endoderm
Blastocoel
Inner endoderm
Embryonal ectoderm
Trophectoderm
Dorsal part
Primitive amnion
EMBRYONAL PARTS
In vitro fertilization – IVF – human embryos
GENERATION OF BLOOD CELLS DURING LIFE SPAN
BEFORE BIRTH
AFTER BIRTH
Cell number (%)
Yolk sac
80
Flat bones
Liver
60
40
Spleen
20
Tubular bones
0
0 1 2 3 4 5 6 7 8 9
10
20
30
40
50
60
70
years
months
BIRTH
BONE MARROW
TRANSPLANTATION
CELL TYPES OF THE BONE MARROW
Stem cells
Osteoblasts
Stromal cells
BONE
csont
Osteoclasts
B-cell precursors
Progenitors
Precursors
Dendritic cell
Central
centrális
sinus
sinus
Blood circulation
Unspecialized stem cells with unlimited proliferating capacity
CD34+ HSC BONE MARROW
MYELOID
LYMPHOID
CMP
CLP
ERYTHROID
BLOOD CELLS
Endothelial cells
Mesenhymal Stem Cells
(MSC)
Other Stem Cells
Fat
Neuronal cells
Epithelial cells of the liver, kidney, skin,
myocytes of the heart and muscle, GI tract
Bone
Cartilage
IMPORTANCE OF TISSUE
STEM CELLS
Self renewal
+
Assimmmetric cell division
At least one differentiated cell
Progenitor/Precursor
More differentiated cell
Progenitors/Precursors
• Continuous replenishment of the hematopoietic system
• Continuous generation of peripheral immune cells
• Circulating progenitors/precursors - BLOOD
• Tissue-specific progenitors/precursors - TISSUES
LIMITED TISSUE – SPECIFIC REGENERATIVE POTENTIAL
SOMATIC CELLS
Telomer length
ARE STEM CELLS EVER YOUNG CELLS?
What about aging?
Replicative scenescence is
inhibited by telomerase
STEM CELLS
Stromal cells – ‘niche’ is
aging as other cell types
The number and the differentiating
capacity of pluripotent stem cells
is decreasing with age
GC, HSC
Telomerase +
SELF RENEWAL AND POTENCY
OF DIFFERENTIATION OF STEM CELLS
IS REGULATED BY:
csont
Stromal
cell
Bone
HSC
Dendritic
cell
Central
sinus
centrális
sinus
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•
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•
•
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HSC – assymetric cell division
self renewal
cell differentiation
The stem cell ‘niche’
Cytokines (LIF, SCF)
Special signalling molecules
JAK – STAT variants
Transcription factors Oct-4
Pluripotency maintaining factor Nanog
HSC self renewing factor Bmi-1
- inhibits the anti-proliferative,
apoptosis promoting factors p16/p19Arf
- enhances telomerase function
PLURIPOTENT BONE MARROW STEM CELLS
REGENERATIVE MEDICINE
Ectodermal
Mesodermal
Endodermal
HMB
Skin
Neuro
A
D
U
L
T
HSC
L
Endothel MSC
M
Pericyte
EPC
Osteoclast
Liver Pancreas Gut
endothel
Bone
Cartilage,
Muscle, Fat
Osteoblast
VASCULO / ANGIOGENESIS
Asahara & Kawamoto 2004 Am J Physiol Cell Physiol
A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT
BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET „NICHE”
Osteoblast
Nestin+MSC
HSC
MSC
HSC
HSC
HSC
Mobilised hematopoetic stem cells (HSC) develop in close contact with
osteoblasts, mesenchymal stem cells (MSC) and endothelial cells
Uccelli A et al. Nat Rev Immunol 2008
COUPLED DEVELOPMENT OF
ENDOTHELIAL AND HEMATOPOETIC
STEM CELLS (HSC)
AORTA
Blood
cell
Biomechanic stress
HSC
GENERATION OF
HEMATOPOETIC CELLS
Adamo et al., Nature 2009, North TE, et al. Cell 2009
BONE MARROW TRANSPLANTATION
Increasing number of bone marrow
transplantations
1990-2007
Csoport
Auto
Allo
• Increasing age limit
• Increased number of typed
donors
• Umbilical cord banks
• Developing countries
• New indications
– Autoimmune diseases
– Tolerance induction
– Regenerative medicine
•Replacement of complex tissues
• Non HSC-derived stem
•Heterogenous cell populations
cells
•Stem- and progenitor cell reservoire in
– adipose tissue-derived MSCadults
•Circulation and migration to tissue
through the blood
•Reverse migration of peripheral immune
Gratwohl & Baldomero Curr Opin Hematol 2009
cells to the bone marrow
MULTIPOTENT MESENCHYMAL STEM CELL
Uccelli A et al. Nat Rev Immunol 2008
Mesenchymal stem cells (MSC) modulate the functions of other cells through
cell – to – cell interactions and through soluble factors produced by them
CHARACTERISTICS AND FUNCTIONS OF MESENCHYMAL
STEM CELLS
• Regulation of bone marrow
HSC
• Integrate to the bone
• Not immunogenic
• Migrate to the site of tissue
demage
• Traverse vessel wall
• Similar action in different
tissues
• Produce trophic and induced
factors
• React to inflammatory signals
• Immune suppressive - GVHD
• Support tumor growth
– Integration
– Immune suppression
• BYSTANDER EFFECTS
– Modulation of demaged tissue
environment
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Inhibition of proliferation
Anti-inflammatory effect
Inhibition of immune cells
Inhibition of apoptosis
Lép
Trophic effects – HSC function
– WNT signaling
– Notch signaling
– Similar effects to bone marrow
functions
– Augmentation of endogenous
regenerative mechanisms
– Low level of integration
– Low level of trans-differentiation
– „Touch and go”
A GYULLADÁSOS FOLYAMATOK ELŐSEGÍTIK A CSONT
LEBONTÁST
INFLAMMATORY T
CELL RESPONSE
BONE
DESORPTION
PROTECTIVE
MECHANISMS
INHIBITION OF BONE
FORMATION
Enhancement
MM
Inhibition
Gátlás
RA
THE INFLAMMATORY CYTOKINE IL-20 PLAYS A ROLE IN BONE
RESORPTION AFTER MENOPAUSE
IL-20 citokine-specific anti-body inhibits RANK receptor expression on
osteoclast precursors and RANKL expression on osteoblasts
Hsu Y-H et al. JEM 2011