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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

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(1)

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

(2)

HEMATOPOIETIC STEM CELLS AND

TRANSDIFFERENTIATIO N

Dr. Péter Balogh and Dr. Péter Engelmann

Transdifferentiation and regenerative medicine – Lecture 6

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

(3)

Issues of hemopoietic differentiation

• Development of hemopoietic system Embryonic

Postnatal

• Regenerating hemopoiesis

• Use of HSCs in non-hemopoietic regenerative

medicine

(4)

Ontogeny of embryonic hemopoietic tissues

Pro-definitive

Primitive Meso-definitive Meta-definitive Adult-definitive E10.5

E7.5 E8.25 E9.0

Hemangioblast Hemogenic Endothelium

Myeloid Lymphoid-Myeloid CFU-s Neonatal HSC

HSC Yolk sac

Allantois Chorion

Allantois

YS blood islands Placenta

AGM

Liver

Placenta

AGM

Liver Yolk sac

Embryo pSP

Umbilical artery

Vitelline artery

Umbilical artery

Vitelline artery

(5)

Evolution of hemopoietic tissues in rodents

Yolk sac

Onset of circulation

Pro

Primitive Meso Meta Adult

E7.5 E8.5 E9.5 E10.5 E11 E11.5 E12.5 E13.5 E14.5 E15 birth

Para-aortic

Splanchnopleura Allantois

Liver

Thymus

Spleen

Bone marrow AGM

Aortic clusters Placenta

(6)

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+

(7)

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

(8)

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)

(9)

Hemopoietic differentiation models

Classic dichotomy model

Modified classic model

Myeloid-based model

Myeloid potential

M

Erythroid potential

E

Megakaryocyte potential

m

T-cell potential

T

B-cell potential

B (CMLP)

M E m

T B M

T 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)

B M M E m T B

M E m

T B M

E m

B M

T M

M M

M T

M

(CMLP) (CMEP)

M E m T B

(10)

Transcriptional regulation of early hemopoietic commitment

Hemangioblasts Hemogenic endothelium

Apoptosis

SCL AML-1 GATA-2 Lmo

PU.1/GATA-3/Ikaros PU.1/GATA-1

CMP

HSC

CLP Notch1

Ikaros HoxB4 GATA-2

Bcl-2 p21

(11)

Transcriptional regulation of myeloid differentiation

Monocyte

Neutrophil

Eosinophil

Erythrocyte

Megakaryocyte

GMP

CMP HSC

EMP PU.1 & GATA-1

PU.1

GATA-1/FOG

ICSBP, PU.1

C/EBP, GATA-1

GATA-1

GATA-1, 2 C/EBP

(12)

Transcriptional regulation of lymphoid differentiation

CLP

Pro-T

PU.1 IL-7R

GM-CSFR

Notch1

Pu.1, E2A

PU.1

Pax5?

EBF Pax5

Early pro-B Late pro-B

Pre-

pro-B D-JH V-D-JH

B cell Monocyte

HSC

(13)

HSC

HSC

HSC

HSC Endothel

Fibroblast

Osteoblast

G-CSF, GM-CSF TPO

TGF

Steady-state and activated haemopoiesis

EPO EPO

IL-1

TNF

Macrophage Bacterial

infection Inflammation

Anemia Hypoxia

HSC

HSC

HSC

HSC SCF, FLT-3I, TPO

Endothel

G-CSF, GM-CSF Fibroblast

Osteoblast

Blood vessel

(14)

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

(15)

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

(16)

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.

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