Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
HEMATOPOIETIC STEM CELLS ANDTRANSDIFFERENTIATION
Dr. Péter Balogh and Dr. Péter EngelmannTransdifferentiation and regenerative medicine – Lecture 6
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
TÁMOP-4.1.2-08/1/A-2009-0011
Issues of hemopoietic differentiation• Development of hemopoietic system
EmbryonicPostnatal
• Regenerating hemopoiesis• Use of HSCs in non-hemopoietic regenerative
medicine
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Ontogeny of embryonic hemopoietic tissues
Pro-definitivePrimitive Meta-definitiveMeso-definitive Adult-definitive
E10.5E7.5 E9.0E8.25
Hemangioblast Hemogenic Endothelium
Myeloid Lymphoid-Myeloid CFU-sNeonatal HSC
HSC
Yolk sacAllantois Chorion
Allantois
YS blood islands
Placenta
AGM
Liver
Placenta
AGM
LiverYolk sacEmbryo pSP
Umbilicalartery
Vitellineartery
Umbilicalartery
Vitellineartery
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Evolution of hemopoietic tissues in rodents
Yolk sac
Onset of circulation
ProPrimitive MetaMeso Adult
E7.5 E8.5 E9.5 E10.5 E11.5 E12.5 E15E13.5 E14.5 birthE11
Para-aorticSplanchnopleura
Allantois
Liver
Thymus
Spleen
Bone marrow
AGM
Aortic clusters
Placenta
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Characteristics of murine embryonic HSCs (AGM/YS/FL)• Leukocyte surface markers: Ly-6A(Sca-1), c-
kit+, CD34+, CD45+, • Shared endothelial markers: CD31+, VE-
cadherin+• TF: Runx1+ SCL+ Gata-2+
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Transcriptional induction of eHSCsIntrinsic 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 modelsClassic dichotomy model
Modified classic model
Myeloid-based model
Myeloid potentialMErythroid potentialE
Megakaryocyte potentialm
T-cell potentialTB-cell potentialB
(CMLP)
M E m
T BMT B
E m
B
M
T
M
(CLP)
(CMEP)
M E m T B
E m
B
M
T
M E m
T B
(CLP)
(CMEP)
BM
M E m T B
M E m
T BM
E m
B
M
T
M
M
M
M
TM
(CMLP)
(CMEP)
M E m T B
TÁMOP-4.1.2-08/1/A-2009-0011Transcriptional regulation of early hemopoietic commitment
Hemangioblasts Hemogenic endothelium
Apoptosis
SCLAML-1GATA-2Lmo
PU.1/GATA-3/IkarosPU.1/GATA-1
CMP
HSC
CLP
Notch1IkarosHoxB4GATA-2
Bcl-2
p21
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Transcriptional regulation of myeloid differentiation
Monocyte
Neutrophil
Eosinophil
Erythrocyte
Megakaryocyte
GMP
CMPHSC
EMP
PU.1 & GATA-1
PU.1
GATA-1/FOG
ICSBP, PU.1
C/EBP, GATA-1
GATA-1
GATA-1, 2
C/EBP
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Transcriptional regulation of lymphoid differentiation
CLP
Pro-T
PU.1IL-7R
GM-CSFR
Notch1
Pu.1, E2A
PU.1
Pax5?EBF Pax5
Early pro-B Late pro-B
Pre-pro-B V-D-JHD-JH
B cell
MonocyteHSC
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HSCHSC
HSCHSC
EndothelFibroblast
Osteoblast
G-CSF, GM-CSF TPOTGF
Steady-state and activated haemopoiesis
EPO
EPO
IL-1TNF
Macrophage
Bacterialinfection
Inflammation
AnemiaHypoxia
HSCHSC
HSCHSC
SCF, FLT-3I, TPOEndothel
G-CSF, GM-CSF
Fibroblast
Osteoblast
Blood vessel
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Human hemopoietic potentialIntraembryonic 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+ progenitorsYolk 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.
