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Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Dr. Péter Balogh and Dr. Péter Engelmann
Transdifferentiation and regenerative medicine –
Lecture 6
HEMATOPOIETIC STEM
CELLS AND
TRANSDIFFERENTIATIO
N
Issues of hemopoietic
differentiation
TÁMOP-4.1.2-08/1/A-2009-0011
• Development of hemopoietic system
Embryonic
Postnatal
• Regenerating hemopoiesis
• Use of HSCs in non-hemopoietic
regenerative medicine
Ontogeny of embryonic
hemopoietic tissues
Chorion
Allantois
YS blood islands
Yolk sac
TÁMOP-4.1.2-08/1/A-2009-0011
Vitelline
artery
Placenta
Placenta
Umbilical
artery
Umbilical
artery
Vitelline
artery
Embryo
Liver
Allantois
E7.5
Hemangioblast
Primitive
pSP
E8.25
AGM
AGM
Yolk sac
E9.0
Liver
E10.5
Hemogenic Endothelium
Pro-definitive Meso-definitive
Meta-definitive Adultdefinitive
Myeloid
Lymphoid-Myeloid
CFU-s
HSC
Neonatal
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Evolution of hemopoietic
tissues in rodents
Yolk sac
Allantois
Placenta
Para-aortic
Splanchnopleura
AGM
Aortic clusters
E7.5
E8.5
E9.5
PrimitivePro Meso Meta
Onset of circulation
E10.5E11 E11.5
E12.5
E13.5
E14.5E15
birth
Adult
Liver
Thymus
Spleen
Bone marrow
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Characteristics of murine
embryonic HSCs (AGM/YS/FL)
• Leukocyte surface markers: Ly-6A(Sca1), c-kit+, CD34+, CD45+,
• Shared endothelial markers: CD31+, VEcadherin+
• TF: Runx1+ SCL+ Gata-2+
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Transcriptional induction
of eHSCs
Intrinsic signals: TF
• Runx1: promotes fetal transition of
hemogenic endothelium into hemopoietic
cells
• GATA-2: sequential promotion of
mesodermal specification,
hemangioblast formation and erythroid
differentiation
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Extrinsic regulation of
eHSCs
Extrinsic signals: interactions with other
germ layer elements
• Yolk sac (endoderm and mesoderm)
• The chorio-allantoic placenta (mesoderm and
trophectoderm)
• AGM region (dorsal ectoderm, mesoderm and
ventral endoderm)
– Ventralizing factors – promote hemopoiesis
(VEGF, bFGF, TGFβ and BMP4)
– Dosalizing factors – antagonize hemopoiesis
(EGF and TGFα)
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Hemopoietic differentiation
models
Classic dichotomy model
Myeloid-based model
E m
E m
M E m
M E m
(CMEP)
M
(CMEP)
M
M E m T B
T
M
M E m T B
T B
T
B
(CLP)
M T
M
Modified classic model
E m
M E m
M
(CMEP)
M E m T B
M
M T B
(CMLP)
M
M T B
(CMLP)
M
M B
B
T
M Myeloid potential
T B
(CLP)
B
T T-cell poten
E Erythroid potential
B B-cell poten
m Megakaryocyte potential
Transcriptional regulation
of early hemopoietic
commitment
TÁMOP-4.1.2-08/1/A-2009-0011
Hemangioblasts Hemogenic endothelium
SCL
AML-1
GATA-2
Lmo
HSC
p21
PU.1/GATA-1
Notch1
Ikaros
HoxB4
GATA-2
PU.1/GATA-3/Ikaros
Bcl-2
CMP
CLP
Apoptosis
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Transcriptional regulation
of myeloid differentiation
ICSBP, PU.1
PU.1
C/EBP
Neutrophil
C/EBP, GATA-1
PU.1 & GATA-1
HSC
GMP
Monocyte
Eosinophil
CMP
GATA-1
GATA-1/FOG
EMP
Erythrocyte
GATA-1, 2
Megakaryocyte
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Transcriptional regulation
of lymphoid differentiation
Pro-T
Notch1
PU.1
IL-7R
HSC
CLP
GM-CSFR
Monocyte
PU.1
Pu.1, E2A
Pax5?
EBF
Prepro-B
Pax5
D-JH
V-D-JH
Early pro-B Late pro-B
B cell
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Steady-state and activated
haemopoiesis
EPO
HSC
Fibroblast
SCF, FLT-3I, TPO
HSC
Osteoblast
Endothel
HSC
G-CSF, GM-CSF
HSC
Anemia
Hypoxia
Blood vessel
EPO
IL-1
TNF
Macrophage
Bacterial
infection
Inflammation
Fibroblast
HSC
G-CSF, GM-CSF
HSC
Osteoblast
Endothel
TPO
TGF
HSC
HSC
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Human hemopoietic potential
Intraembryonic sources and potential:
• D19: HPP in embryo in the absence of
detectable CD34+ hematopoietic cells,
and spanned both lymphoid and myeloid
lineages
• D24: in the splanchnopleural mesoderm
• D27: aorta with CD34+ progenitors
Yolk sac: only myelopoiesis starting at
around the 3rd week
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Other potential uses of
hemopoietic stem cells
• Regenerative medicine in parenchymal
tissues: muscle, neural tissues,
liver, etc.
• Sources: adult or embryonic (umbilical
vein mononuclear cells)
• Experimental settings: use of
genetically marked cells or inducible
Cre-Lox transgenic animals, and their
detection in damaged/regenerating
tissues
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Summary
• Hemopoiesis is established in successive
waves at various anatomical locations, where
hemopoietic activities at different host
tissues result in diverse cellular progeny.
• The hemopoietic committment is under the
combined effects of endogenous programing and
external signals, where latter elements may
alter the steady-state hemopoiesis.
• Hemopoietic stem cells may promote the
regeneration of non-hemopoietic tissues by
(a) promoting vascular repair, (b) tissue
repair and (c) possible transdifferentiation.